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    Clinical Trial Results:
    A randomised, double-blind, double-dummy, placebo and active-controlled, three-way crossover study to evaluate the safety, tolerability and efficacy of 28-day inhaled CHF 6001 DPI (1200 microgrammes daily) in subjects with COPD.

    Summary
    EudraCT number
    2012-001005-25
    Trial protocol
    GB  
    Global end of trial date
    25 Oct 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    29 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of Sponsor public contact and scientific contact.

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-1201-PR-0079
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01730404
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo, 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., ClinicalTrials_info@chiesi.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
    25 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: - to evaluate the effect of CHF 6001 DPI on biological markers of inflammation in induced sputum and in the blood, and on pulmonary function. - to evaluate the safety and tolerability of CHF 6001 DPI after 28 days of inhaled dosing. - to assess the blood PK profile of CHF6001 and its metabolite at steady-state in GOLD stage 2-3 COPD patients.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements . Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 55
    Worldwide total number of subjects
    55
    EEA total number of subjects
    55
    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)
    43
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Fifty-five patients were actually randomised into the study; following the randomization 13 patients were withdrawn due to adverse events (AE), and 5 patients withdrew their consent for participation. All 55 patients were analysed as part of the Safety population. Fifty-three patients were analysed as part of the modified ITT population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence C--R--P
    Arm description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg administered using Aerolizer® DPI; giving a total dose of 1200 μg of CHF 6001

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

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

    Arm title
    Sequence P--C--R
    Arm description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg administered using Aerolizer® DPI; giving a total dose of 1200 μg of CHF 6001

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

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

    Arm title
    Sequence R--P--C
    Arm description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

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

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001

    Arm title
    Sequence C--P--R
    Arm description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg; giving a total dose of 1200 μg of CHF 6001

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

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

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

    Arm title
    Sequence P--R--C
    Arm description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

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

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001

    Arm title
    Sequence R--C--P
    Arm description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet Roflumilast 500 μg; giving a total dose of 500μg of Roflumilast

    Investigational medicinal product name
    CHF 6001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 400 μg ; giving a total dose of 1200 μg of CHF 6001

    Investigational medicinal product name
    CHF 6001 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    3 inhalations of CHF 6001 Placebo DPI

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

    Number of subjects in period 1
    Sequence C--R--P Sequence P--C--R Sequence R--P--C Sequence C--P--R Sequence P--R--C Sequence R--C--P
    Started
    10
    10
    8
    9
    8
    10
    Completed
    6
    7
    4
    9
    5
    6
    Not completed
    4
    3
    4
    0
    3
    4
         Adverse event, non-fatal
    3
    2
    4
    -
    2
    2
         Consent withdrawn by subject
    1
    1
    -
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence C--R--P
    Reporting group description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence P--C--R
    Reporting group description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence R--P--C
    Reporting group description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence C--P--R
    Reporting group description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence P--R--C
    Reporting group description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence R--C--P
    Reporting group description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group values
    Sequence C--R--P Sequence P--C--R Sequence R--P--C Sequence C--P--R Sequence P--R--C Sequence R--C--P Total
    Number of subjects
    10 10 8 9 8 10 55
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.5 ± 7.25 61.7 ± 6.46 59.4 ± 5.71 55.2 ± 7.14 60.5 ± 5.32 59.3 ± 5.79 -
    Gender categorical
    Units: Subjects
        Female
    5 4 5 3 5 3 25
        Male
    5 6 3 6 3 7 30
    Subject analysis sets

    Subject analysis set title
    Test treatment - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Reference treatment - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Placebo - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Test treatment - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment

    Subject analysis set title
    Reference treatment - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.

    Subject analysis set title
    Placebo - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.

    Subject analysis set title
    Test treatment - PK population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All subjects from the safety population excluding subjects without any valid PK measurement and with major Protocol deviations affecting the PK evaluations

    Subject analysis sets values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population Test treatment - PK population
    Number of subjects
    42
    49
    43
    42
    47
    43
    40
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    16
    21
    16
    16
    19
    16
    16
        Male
    26
    28
    27
    26
    28
    27
    24

    End points

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    End points reporting groups
    Reporting group title
    Sequence C--R--P
    Reporting group description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence P--C--R
    Reporting group description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence R--P--C
    Reporting group description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence C--P--R
    Reporting group description
    • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence P--R--C
    Reporting group description
    • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Reporting group title
    Sequence R--C--P
    Reporting group description
    • Reference treatment (R): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast 500 μg; giving a total dose of 500 μg of Roflumilast • Test treatment (C): 3 inhalations of CHF 6001 400 μg + 1 tablet Roflumilast Placebo; giving a total dose of 1200 μg of CHF 6001 • Placebo (P): 3 inhalations of CHF 6001 Placebo DPI + 1 tablet Roflumilast Placebo After a 15 ±2 days run-in Period, patients were randomised to receive CHF 6001 1200μg using Aerolizer® DPI (T), Roflumilast 500μg (Daxas®) (R) or matched Placebo daily in the morning for 28 days, according to the above sequence. Each treatment period was separated from the other by a wash-out Period of 4-5 weeks.

    Subject analysis set title
    Test treatment - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Reference treatment - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Placebo - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomised subjects who will take at least one administration of study medication

    Subject analysis set title
    Test treatment - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment

    Subject analysis set title
    Reference treatment - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.

    Subject analysis set title
    Placebo - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who take at least one administration of study medication and with at least one post-baseline efficacy assessment.

    Subject analysis set title
    Test treatment - PK population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All subjects from the safety population excluding subjects without any valid PK measurement and with major Protocol deviations affecting the PK evaluations

    Primary: Total cell count

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    End point title
    Total cell count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline was used in the analyses and reported here (see Table 14.2.1.4). This is an exploratory study therefore the objectives and the endpoints have not been identified as either primary or secondary.
    End point type
    Primary
    End point timeframe
    Total cell count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: millions cells/g sputum
        arithmetic mean (standard deviation)
    2.7301 ± 8.58667
    -0.6251 ± 17.58909
    1.0149 ± 13.52405
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.6544
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.912
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.605
         upper limit
    1.376
    Notes
    [1] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Placebo - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.0835
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.673
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4292
         upper limit
    1.0564
    Notes
    [2] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.1875
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.355
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8571
         upper limit
    2.1422
    Notes
    [3] - This is a "proof of concept" study: no statistical hypothesis is included

    Secondary: Basophils

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    End point title
    Basophils
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    -0.01 ± 0.028
    0 ± 0.03
    0 ± 0.023
    No statistical analyses for this end point

    Secondary: Basophils/Leukocytes

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    End point title
    Basophils/Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    38
    43
    39
    Units: percent
        arithmetic mean (standard deviation)
    0 ± 0.29
    -0.1 ± 0.24
    0 ± 0.27
    No statistical analyses for this end point

    Secondary: Eosinophils

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    End point title
    Eosinophils
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.01 ± 0.104
    0.02 ± 0.102
    0.07 ± 0.173
    No statistical analyses for this end point

    Secondary: Eosinophis/Leukocytes

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    End point title
    Eosinophis/Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    38
    43
    39
    Units: percent
        arithmetic mean (standard deviation)
    0.1 ± 1.39
    0 ± 1.27
    0.8 ± 2.06
    No statistical analyses for this end point

    Secondary: Erythrocytes

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    End point title
    Erythrocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^12/L
        arithmetic mean (standard deviation)
    0.015 ± 0.1844
    0.005 ± 0.2089
    0.022 ± 0.2293
    No statistical analyses for this end point

    Secondary: Hematocrit

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    End point title
    Hematocrit
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: ratio
        arithmetic mean (standard deviation)
    -0.001 ± 0.0177
    -0.003 ± 0.0183
    -0.001 ± 0.0201
    No statistical analyses for this end point

    Secondary: Hemoglobin

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    End point title
    Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: g/dL
        arithmetic mean (standard deviation)
    -0.05 ± 0.567
    -0.15 ± 0.607
    -0.1 ± 0.669
    No statistical analyses for this end point

    Secondary: Leukocytes

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    End point title
    Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.35 ± 1.673
    0.39 ± 1.345
    0.33 ± 1.517
    No statistical analyses for this end point

    Secondary: Lymphocytes

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    End point title
    Lymphocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.18 ± 0.439
    0.21 ± 0.457
    0.12 ± 0.453
    No statistical analyses for this end point

    Secondary: Lymphocytes/Leukocytes

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    End point title
    Lymphocytes/Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    38
    43
    39
    Units: percent
        arithmetic mean (standard deviation)
    1.5 ± 5.18
    1.3 ± 6.34
    0.6 ± 6.44
    No statistical analyses for this end point

    Secondary: Monocytes

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    End point title
    Monocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    Units: 10^9/L
        arithmetic mean (standard deviation)
    -0.04 ± 0.183
    0 ± 0.121
    -0.01 ± 0.176
    No statistical analyses for this end point

    Secondary: Monocytes/Leukocytes

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    End point title
    Monocytes/Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    38
    43
    39
    Units: percent
        arithmetic mean (standard deviation)
    -0.8 ± 1.68
    -0.5 ± 1.46
    -0.6 ± 1.58
    No statistical analyses for this end point

    Secondary: Neutrophils

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    End point title
    Neutrophils
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    0.18 ± 1.479
    0.16 ± 1.237
    0.15 ± 1.325
    No statistical analyses for this end point

    Secondary: Neutrophils/Leukocytes

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    End point title
    Neutrophils/Leukocytes
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    38
    43
    39
    Units: percent
        arithmetic mean (standard deviation)
    -0.8 ± 5.58
    -0.6 ± 7.09
    -0.8 ± 6.69
    No statistical analyses for this end point

    Secondary: Platelets

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    End point title
    Platelets
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: 10^9/L
        arithmetic mean (standard deviation)
    2.25 ± 19.847
    13.44 ± 32.017
    -1.46 ± 23.999
    No statistical analyses for this end point

    Secondary: Alanine aminotransferase

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    End point title
    Alanine aminotransferase
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: U/L
        arithmetic mean (standard deviation)
    -1.19 ± 7.895
    -2.4 ± 6.13
    -0.94 ± 9.66
    No statistical analyses for this end point

    Secondary: Albumin

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    End point title
    Albumin
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: g/L
        arithmetic mean (standard deviation)
    -0.5 ± 2.192
    -0.17 ± 2.533
    -0.2 ± 2.131
    No statistical analyses for this end point

    Secondary: Akaline phosphatase

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    End point title
    Akaline phosphatase
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: U/L
        arithmetic mean (standard deviation)
    -0.63 ± 9.352
    1.7 ± 9.028
    1.49 ± 7.882
    No statistical analyses for this end point

    Secondary: Aspartate amintransferase

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    End point title
    Aspartate amintransferase
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    39
    44
    37
    Units: U/L
        arithmetic mean (standard deviation)
    0.51 ± 8.583
    -1.2 ± 5.03
    0.7 ± 6.479
    No statistical analyses for this end point

    Secondary: Bilirubin

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    End point title
    Bilirubin
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: μmol/L
        arithmetic mean (standard deviation)
    -0.51 ± 3.948
    -0.48 ± 3.003
    0.01 ± 3.078
    No statistical analyses for this end point

    Secondary: Calcium

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    End point title
    Calcium
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    44
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.01 ± 0.1175
    0.016 ± 0.0957
    -0.01 ± 0.0827
    No statistical analyses for this end point

    Secondary: Chloride

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    End point title
    Chloride
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    37
    44
    36
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.14 ± 2.702
    -0.58 ± 2.281
    -0.23 ± 2.496
    No statistical analyses for this end point

    Secondary: Creatinine

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    End point title
    Creatinine
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: μmol/L
        arithmetic mean (standard deviation)
    -0.9 ± 6.183
    -0.18 ± 7.565
    -1.32 ± 6.274
    No statistical analyses for this end point

    Secondary: Gamma glutamyl transferase

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    End point title
    Gamma glutamyl transferase
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    39
    44
    40
    Units: U/L
        arithmetic mean (standard deviation)
    -1.44 ± 8.542
    -0.76 ± 11.551
    -1.37 ± 12.08
    No statistical analyses for this end point

    Secondary: Glucose

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    End point title
    Glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    39
    44
    40
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.187 ± 0.6213
    0.167 ± 0.5524
    0.212 ± 0.9286
    No statistical analyses for this end point

    Secondary: Phosphate

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    End point title
    Phosphate
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.039 ± 0.1867
    0.039 ± 0.1487
    0.028 ± 0.1309
    No statistical analyses for this end point

    Secondary: Potassium

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    End point title
    Potassium
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.14 ± 0.3181
    -0.049 ± 0.523
    -0.124 ± 0.3382
    No statistical analyses for this end point

    Secondary: Protein

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    End point title
    Protein
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    40
    Units: g/L
        arithmetic mean (standard deviation)
    -0.09 ± 3.775
    0.27 ± 3.547
    0.43 ± 3.083
    No statistical analyses for this end point

    Secondary: Sodium

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    End point title
    Sodium
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    40
    45
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    0 ± 2.1
    -0.3 ± 2.09
    -0.2 ± 2.06
    No statistical analyses for this end point

    Secondary: Urate

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    End point title
    Urate
    End point description
    End point type
    Secondary
    End point timeframe
    Routine hematology and chemistry were performed at screening and Day 28.
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    35
    40
    36
    Units: μmol/L
        arithmetic mean (standard deviation)
    -2.94 ± 31.936
    -12.15 ± 37.216
    -11.09 ± 31.245
    No statistical analyses for this end point

    Other pre-specified: Neutrophils - absolute count

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    End point title
    Neutrophils - absolute count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline was used in the analyses and reported here (see Table 14.2.1.5)
    End point type
    Other pre-specified
    End point timeframe
    Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: millions neutrophils/g sputum
        arithmetic mean (standard deviation)
    2.6588 ± 8.28804
    -0.647 ± 17.43528
    0.8679 ± 13.13533
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.565
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.879
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5611
         upper limit
    1.3774
    Notes
    [4] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.2238
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.358
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.823
         upper limit
    2.241
    Notes
    [5] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.0815
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.647
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3958
         upper limit
    1.0587
    Notes
    [6] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Neutrophils - differential count

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    End point title
    Neutrophils - differential count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and reported here (see Table 14.2.1.9 of CSR))
    End point type
    Other pre-specified
    End point timeframe
    Neutrophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: percent
        arithmetic mean (standard deviation)
    0.4409 ± 14.89339
    -5.5694 ± 13.66577
    -1.0944 ± 16.06526
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.1779
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.953
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.888
         upper limit
    1.023
    Notes
    [7] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.2549
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.957
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.885
         upper limit
    1.0339
    Notes
    [8] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.9277
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.996
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9208
         upper limit
    1.0783
    Notes
    [9] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Eosinophils - absolute count

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    End point title
    Eosinophils - absolute count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and reported here (see Table 14.2.1.6 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: millions eosinophils /g sputum
        arithmetic mean (standard deviation)
    0.0117 ± 1.19362
    -0.0099 ± 0.08537
    0.0498 ± 0.30105
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1521
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.241
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0335
         upper limit
    1.7296
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.5608
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.536
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0626
         upper limit
    4.5957
    Notes
    [10] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.4489
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.449
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0541
         upper limit
    3.7301
    Notes
    [11] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Eosinophils - differential count

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    End point title
    Eosinophils - differential count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.10 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    Eosinophil count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: percent
        arithmetic mean (standard deviation)
    -0.6263 ± 6.22173
    0.5386 ± 2.328
    1.3458 ± 4.51746
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.2485
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.238
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    2.8363
    Notes
    [12] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.9687
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.949
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0639
         upper limit
    14.094
    Notes
    [13] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    = 0.2957
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.251
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.018
         upper limit
    3.5089
    Notes
    [14] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Macrophages - absolute count

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    End point title
    Macrophages - absolute count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.7 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: millions macrophages/g sputum
        arithmetic mean (standard deviation)
    0.1048 ± 0.70455
    0.0231 ± 0.77945
    0.0961 ± 1.01861
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.9379
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.983
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6379
         upper limit
    1.5159
    Notes
    [15] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    P-value
    = 0.3588
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.808
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5069
         upper limit
    1.2864
    Notes
    [16] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    P-value
    = 0.4097
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.218
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7549
         upper limit
    1.9643
    Notes
    [17] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Macrophages - differential count

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    End point title
    Macrophages - differential count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.11 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    Macrophage count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: percent
        arithmetic mean (standard deviation)
    0.4879 ± 14.69496
    5.4444 ± 11.80631
    -0.7194 ± 14.45761
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    = 0.9551
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6219
         upper limit
    1.6526
    Notes
    [18] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    = 0.3048
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.296
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7826
         upper limit
    2.1468
    Notes
    [19] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    = 0.3574
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.782
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4586
         upper limit
    1.3338
    Notes
    [20] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Lymphocytes - absolute count

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    End point title
    Lymphocytes - absolute count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table of 14.2.1.8 CSR)
    End point type
    Other pre-specified
    End point timeframe
    Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: millions lymphocytes/g sputum
        arithmetic mean (standard deviation)
    -0.0017 ± 0.01046
    0.001 ± 0.00567
    0.0004 ± 0.00152
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    P-value
    = 0.146
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    4.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    27.6916
    Notes
    [21] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    P-value
    = 0.2756
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    2.913
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4121
         upper limit
    20.5843
    Notes
    [22] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.741
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.399
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1817
         upper limit
    10.7785
    Notes
    [23] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Lymphocytes - differential count

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    End point title
    Lymphocytes - differential count
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.12 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    Lymphocyte count in sputum was performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: percent
        arithmetic mean (standard deviation)
    -0.047 ± 0.21348
    0.0046 ± 0.08674
    0.0222 ± 0.09268
    Statistical analysis title
    CHF 6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [24]
    P-value
    = 0.1235
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    8.409
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5454
         upper limit
    129.647
    Notes
    [24] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    P-value
    = 0.3513
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    3.701
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2237
         upper limit
    61.2316
    Notes
    [25] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF 6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [26]
    P-value
    = 0.571
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    2.272
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1244
         upper limit
    41.5049
    Notes
    [26] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: IL-8 in sputum supernatant

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    End point title
    IL-8 in sputum supernatant
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.13 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    The level of IL-8 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: pg/mL
        arithmetic mean (standard deviation)
    152.9594 ± 2546.18
    -923.286 ± 2862.978
    462.8729 ± 3054.962
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    P-value
    = 0.0039
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.718
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5792
         upper limit
    0.8908
    Notes
    [27] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Placebo - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [28]
    P-value
    = 0.0014
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.671
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5333
         upper limit
    0.845
    Notes
    [28] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [29]
    P-value
    = 0.602
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8228
         upper limit
    1.3915
    Notes
    [29] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: IL-6 in sputum supernatant

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    End point title
    IL-6 in sputum supernatant
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.14 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    The level of IL-6 in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: pg/mL
        arithmetic mean (standard deviation)
    54.1723 ± 212.7271
    17.2294 ± 137.5087
    -20.7899 ± 92.10865
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [30]
    P-value
    = 0.0801
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.373
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9604
         upper limit
    1.9617
    Notes
    [30] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [31]
    P-value
    = 0.7928
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6502
         upper limit
    1.3932
    Notes
    [31] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [32]
    P-value
    = 0.0724
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.442
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9652
         upper limit
    2.155
    Notes
    [32] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Neutrophil elastase in sputum supernatant

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    End point title
    Neutrophil elastase in sputum supernatant
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.15 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    The level of neutrophil elastase in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: pg/mL
        arithmetic mean (standard deviation)
    -215988 ± 1657361
    -575067 ± 1738260
    -473269 ± 1463202
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [33]
    P-value
    = 0.0773
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4706
         upper limit
    1.0418
    Notes
    [33] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [34]
    P-value
    = 0.0034
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3623
         upper limit
    0.8049
    Notes
    [34] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [35]
    P-value
    = 0.2322
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.297
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8408
         upper limit
    1.9997
    Notes
    [35] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Myeloperoxidase in sputum supernatant

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    End point title
    Myeloperoxidase in sputum supernatant
    End point description
    Data from Day 21, Day 24 and Day 28 were averaged and change from baseline were used in the analyses and are reported here (see Table 14.2.1.16 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    The level of myeloperoxidase in sputum supernatant were performed on Day 1 (baseline values), Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: ng/mL
        arithmetic mean (standard deviation)
    -4.2085 ± 1347.198
    -402.997 ± 1347.198
    -402.997 ± 1604.78
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Placebo - mITT population v Test treatment - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [36]
    P-value
    = 0.0368
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.676
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4693
         upper limit
    0.975
    Notes
    [36] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [37]
    P-value
    = 0.0086
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.589
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3997
         upper limit
    0.8672
    Notes
    [37] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [38]
    P-value
    = 0.5117
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.149
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7517
         upper limit
    1.7561
    Notes
    [38] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in serum fibrinogen

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    End point title
    Change from baseline to Day 28 in serum fibrinogen
    End point description
    Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.4 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: ug/L
        arithmetic mean (standard deviation)
    91.0237 ± 466.5769
    98.4042 ± 572.3796
    57.6753 ± 571.7863
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [39]
    P-value
    = 0.0646
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.889
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7846
         upper limit
    1.0073
    Notes
    [39] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [40]
    P-value
    = 0.4629
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.956
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8456
         upper limit
    1.0801
    Notes
    [40] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [41]
    P-value
    = 0.2416
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8233
         upper limit
    1.051
    Notes
    [41] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in serum CRP

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    End point title
    Change from baseline to Day 28 in serum CRP
    End point description
    Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.1 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.391 ± 44.4402
    15.331 ± 173.3361
    -72.364 ± 381.2791
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [42]
    P-value
    = 0.553
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.902
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6382
         upper limit
    1.2746
    Notes
    [42] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [43]
    P-value
    = 0.5279
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.898
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6389
         upper limit
    1.2612
    Notes
    [43] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [44]
    P-value
    = 0.9774
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7182
         upper limit
    1.4057
    Notes
    [44] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in blood IL-6

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    End point title
    Change from baseline to Day 28 in blood IL-6
    End point description
    Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.2 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: pg/mL
        arithmetic mean (standard deviation)
    0.3074 ± 1.32279
    0.281 ± 1.79656
    -1.0879 ± 2.77641
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [45]
    P-value
    = 0.1517
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9549
         upper limit
    1.3375
    Notes
    [45] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [46]
    P-value
    = 0.3013
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.091
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9229
         upper limit
    1.2908
    Notes
    [46] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [47]
    P-value
    = 0.6741
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8783
         upper limit
    1.2208
    Notes
    [47] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in blood IL-8

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    End point title
    Change from baseline to Day 28 in blood IL-8
    End point description
    Data on change from baseline to Day 28 were used in the analyses and are reported here (see Table 14.2.2.3 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: pg/mL
        arithmetic mean (standard deviation)
    0.0747 ± 4.90551
    -2.7426 ± 10.89529
    -3.8656 ± 7.08697
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [48]
    P-value
    = 0.0556
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.157
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9964
         upper limit
    1.3435
    Notes
    [48] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [49]
    P-value
    = 0.8286
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.882
         upper limit
    1.1688
    Notes
    [49] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [50]
    P-value
    = 0.0736
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.987
         upper limit
    1.3157
    Notes
    [50] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline in pre-bronchodilator FEV1

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    End point title
    Change from baseline in pre-bronchodilator FEV1
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.3.1. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 9, Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.054 ± 0.2149
    0.035 ± 0.1703
    -0.044 ± 0.2219
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [51]
    P-value
    = 0.6328
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0447
         upper limit
    0.073
    Notes
    [51] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [52]
    P-value
    = 0.0631
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0031
         upper limit
    0.1121
    Notes
    [52] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [53]
    P-value
    = 0.1789
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    -0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0996
         upper limit
    0.0189
    Notes
    [53] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline in post-bronchodilator FEV1

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    End point title
    Change from baseline in post-bronchodilator FEV1
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (sse tab.
    End point type
    Other pre-specified
    End point timeframe
    At Day 9, Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.067 ± 0.2459
    0.025 ± 0.1851
    -0.068 ± 0.2136
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [54]
    P-value
    = 0.8615
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    -0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0652
         upper limit
    0.0547
    Notes
    [54] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [55]
    P-value
    = 0.6931
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0483
         upper limit
    0.0723
    Notes
    [55] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [56]
    P-value
    = 0.5734
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    -0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.078
         upper limit
    0.0435
    Notes
    [56] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline in pre-bronchodilator FVC

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    End point title
    Change from baseline in pre-bronchodilator FVC
    End point description
    Only data on change from Day 1 (baseline) to Day 28 is reported here (see tab. 14.2.3.2 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: Liter
        arithmetic mean (standard deviation)
    -0.079 ± 0.2833
    0.06 ± 0.3552
    -0.109 ± 0.3519
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [57]
    P-value
    = 0.2267
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0371
         upper limit
    0.154
    Notes
    [57] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [58]
    P-value
    = 0.0292
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.105
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.0109
         upper limit
    0.1994
    Notes
    [58] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [59]
    P-value
    = 0.3315
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    -0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1421
         upper limit
    0.0486
    Notes
    [59] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline in post-bronchodilator FVC

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    End point title
    Change from baseline in post-bronchodilator FVC
    End point description
    Only data on change from Day 1 (baseline) to Day 28 is reported here (tab. 14.2.3.2 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 9, Day 21, Day 24 and Day 28.
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.135 ± 0.3188
    0.007 ± 0.347
    -0.128 ± 0.2882
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [60]
    P-value
    = 0.6355
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0743
         upper limit
    0.121
    Notes
    [60] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [61]
    P-value
    = 0.4213
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    0.039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0578
         upper limit
    0.1368
    Notes
    [61] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [62]
    P-value
    = 0.7455
    Method
    ANCOVA
    Parameter type
    least square mean
    Point estimate
    -0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.115
         upper limit
    0.0827
    Notes
    [62] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in VC

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    End point title
    Change from baseline to Day 28 in VC
    End point description
    Only data on change from baseline to Day 28 are reported here (see tab. 14.2.4..1 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 1 and Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    0.0013 ± 0.50406
    0.0612 ± 0.29528
    0.0853 ± 0.34144
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [63]
    P-value
    = 0.3709
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.984
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9494
         upper limit
    1.0198
    Notes
    [63] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [64]
    P-value
    = 0.243
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9857
         upper limit
    1.0575
    Notes
    [64] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [65]
    P-value
    = 0.0311
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.964
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9321
         upper limit
    0.9965
    Notes
    [65] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in IC

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    End point title
    Change from baseline to Day 28 in IC
    End point description
    Only data on change from baseline to Day 28 are reported here (see tab 14.2.4.2).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    0.0354 ± 0.43351
    0.0312 ± 0.37439
    0.0017 ± 0.40019
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [66]
    P-value
    = 0.5088
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.982
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9314
         upper limit
    1.0362
    Notes
    [66] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [67]
    P-value
    = 0.5606
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.985
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9341
         upper limit
    1.038
    Notes
    [67] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [68]
    P-value
    = 0.9306
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.998
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9469
         upper limit
    1.0512
    Notes
    [68] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in RV

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    End point title
    Change from baseline to Day 28 in RV
    End point description
    Only data on change from baseline to Day 28 are reported here (see tab. 14.2.4.3 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.0587 ± 1.08645
    0.016 ± 0.58512
    0.0097 ± 0.63798
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [69]
    P-value
    = 0.6873
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9583
         upper limit
    1.0664
    Notes
    [69] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [70]
    P-value
    = 0.1946
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.965
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9152
         upper limit
    1.0186
    Notes
    [70] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [71]
    P-value
    = 0.0796
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9944
         upper limit
    1.1024
    Notes
    [71] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in FRC

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    End point title
    Change from baseline to Day 28 in FRC
    End point description
    Data on change from baseline to Day 28 are reported here (see table 14.2.4.4 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.0726 ± 0.99242
    0.0607 ± 0.48505
    0.0867 ± 0.60328
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [72]
    P-value
    = 0.9914
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9635
         upper limit
    1.0383
    Notes
    [72] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [73]
    P-value
    = 0.9262
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.998
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.962
         upper limit
    1.036
    Notes
    [73] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [74]
    P-value
    = 0.9154
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9664
         upper limit
    1.0387
    Notes
    [74] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change form baseline to Day 28 in TLC

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    End point title
    Change form baseline to Day 28 in TLC
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.5. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.0564 ± 0.79366
    0.0723 ± 0.53586
    0.0956 ± 0.62812
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [75]
    P-value
    = 0.696
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.995
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9706
         upper limit
    1.0202
    Notes
    [75] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3702 [76]
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.989
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9648
         upper limit
    1.0136
    Notes
    [76] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHf6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [77]
    P-value
    = 0.6072
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9823
         upper limit
    1.0309
    Notes
    [77] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in RV/TLC

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    End point title
    Change from baseline to Day 28 in RV/TLC
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.6 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: percent
        arithmetic mean (standard deviation)
    0.1 ± 8.01
    -0.2 ± 4.38
    -0.4 ± 5.37
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [78]
    P-value
    = 0.3623
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9797
         upper limit
    1.057
    Notes
    [78] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [79]
    P-value
    = 0.2407
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.978
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9416
         upper limit
    1.0155
    Notes
    [79] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [80]
    P-value
    = 0.311
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.0037
         upper limit
    1.0789
    Notes
    [80] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in ITV

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    End point title
    Change from baseline to Day 28 in ITV
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.7. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: liters
        arithmetic mean (standard deviation)
    -0.0267 ± 0.91372
    -0.0112 ± 0.48576
    0.0822 ± 0.57956
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [81]
    P-value
    = 0.7135
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.994
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9604
         upper limit
    1.0282
    Notes
    [81] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [82]
    P-value
    = 0.5332
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9572
         upper limit
    1.0231
    Notes
    [82] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [83]
    P-value
    = 0.8037
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9713
         upper limit
    1.0381
    Notes
    [83] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change from baseline to Day 28 in sGAW

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    End point title
    Change from baseline to Day 28 in sGAW
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.8. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: kPa/s
        arithmetic mean (standard deviation)
    0 ± 0.2071
    0.0302 ± 0.1805
    0.0086 ± 0.27717
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [84]
    P-value
    = 0.4104
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.845
         upper limit
    1.0721
    Notes
    [84] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    roflumilast vs placebo
    Comparison groups
    Placebo - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [85]
    P-value
    = 0.2505
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9518
         upper limit
    1.2046
    Notes
    [85] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [86]
    P-value
    = 0.0445
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.889
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7925
         upper limit
    0.997
    Notes
    [86] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Change form baseline to Day 28 in GAW

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    End point title
    Change form baseline to Day 28 in GAW
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.4.9. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: kPa*s/liters
        arithmetic mean (standard deviation)
    -0.0003 ± 0.17315
    -0.0388 ± 0.16972
    -0.0051 ± 0.08507
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [87]
    P-value
    = 0.3202
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.947
         upper limit
    1.1782
    Notes
    [87] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [88]
    P-value
    = 0.3705
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.855
         upper limit
    1.061
    Notes
    [88] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [89]
    P-value
    = 0.0531
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9986
         upper limit
    1.2318
    Notes
    [89] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: TDI scores on Day 28

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    End point title
    TDI scores on Day 28
    End point description
    Only data on change from Day 1 (baseline) to Day 28 are reported here (See tab. 14.2.5.1. of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: integer
        arithmetic mean (standard deviation)
    0.2 ± 0.7
    0.2 ± 0.57
    0 ± 0.42
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [90]
    P-value
    = 0.3202
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.947
         upper limit
    1.1782
    Notes
    [90] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [91]
    P-value
    = 0.3705
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    0.952
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.855
         upper limit
    1.061
    Notes
    [91] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [92]
    P-value
    = 0.0531
    Method
    ANCOVA
    Parameter type
    geometric LSM
    Point estimate
    1.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9986
         upper limit
    1.2318
    Notes
    [92] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: Rescue drug use over the 28-day period

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    End point title
    Rescue drug use over the 28-day period
    End point description
    Rescue drug use was expressed as mean number of puffs/day of salbutamol resue medication. Data on table 14.2.6. of CSR are reported here.
    End point type
    Other pre-specified
    End point timeframe
    Throughout the 28-day period
    End point values
    Test treatment - mITT population Reference treatment - mITT population Placebo - mITT population
    Number of subjects analysed
    42
    47
    43
    Units: puffs/day
        arithmetic mean (standard deviation)
    1.71 ± 2.244
    2.11 ± 2.667
    1.99 ± 2.583
    Statistical analysis title
    CHF6001 vs placebo
    Comparison groups
    Test treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    other [93]
    P-value
    = 0.1185
    Method
    ANOVA
    Parameter type
    least square mean
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.521
         upper limit
    0.06
    Notes
    [93] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    Roflumilast vs placebo
    Comparison groups
    Reference treatment - mITT population v Placebo - mITT population
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other [94]
    P-value
    = 0.9173
    Method
    ANOVA
    Parameter type
    least square mean
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.269
         upper limit
    0.299
    Notes
    [94] - This is a "proof of concept" study: no statistical hypothesis is included
    Statistical analysis title
    CHF6001 vs Roflumilast
    Comparison groups
    Test treatment - mITT population v Reference treatment - mITT population
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [95]
    P-value
    = 0.0904
    Method
    ANOVA
    Parameter type
    least square mean
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    0.04
    Notes
    [95] - This is a "proof of concept" study: no statistical hypothesis is included

    Other pre-specified: FEV1 on Day 1

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    End point title
    FEV1 on Day 1
    End point description
    FEV1, to assess potential occurrence of paradoxical bronchospasm on Day 1 (2-hour spirometry measurement). Absolute change values are reported here (sse table 14.3.9 of CSR)
    End point type
    Other pre-specified
    End point timeframe
    On Day 1 (2-hour spirometry measurement)
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: liters
        arithmetic mean (standard deviation)
    0.254 ± 0.1532
    0.246 ± 0.1853
    0.233 ± 0.158
    No statistical analyses for this end point

    Other pre-specified: Heart rate

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    End point title
    Heart rate
    End point description
    Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data on Day 28, 10 hours post-dose are reported here (See tab. 14.3.6.1.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: bpm
        arithmetic mean (standard deviation)
    73.9 ± 12.89
    76.6 ± 11.5
    74 ± 11.36
    No statistical analyses for this end point

    Other pre-specified: Systolic blood pressure

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    End point title
    Systolic blood pressure
    End point description
    Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data from 10 hours post-dose measurement at Day 28 are reported here (sse table 14.3.6.2.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    On Day 1 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: mmHg
        arithmetic mean (standard deviation)
    128.6 ± 18.99
    129.3 ± 16.73
    134.9 ± 16.47
    No statistical analyses for this end point

    Other pre-specified: Diastolic blood pressure

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    End point title
    Diastolic blood pressure
    End point description
    Vital signs (HR and BP) were assessed after 5 min in supine position at pre-dose, 30 minutes, and 1, 2, 3, 6, 8 and 10 hours post-dose. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.6.3.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    On Day 1 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: mmHg
        arithmetic mean (standard deviation)
    73.6 ± 12.37
    72.1 ± 11.04
    74.6 ± 10.95
    No statistical analyses for this end point

    Other pre-specified: Body weight

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    End point title
    Body weight
    End point description
    Only data at Day 28 are reported here (see table 14.3.8 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    On Day 1 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: kg
        arithmetic mean (standard deviation)
    74.62 ± 16.446
    74.7 ± 15.971
    76.19 ± 16.868
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG HR

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    End point title
    12-lead ECG HR
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.1.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: bpm
        arithmetic mean (standard deviation)
    74.4 ± 12.22
    76 ± 11.5
    74.8 ± 11.22
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG PR

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    End point title
    12-lead ECG PR
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.2.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: msec
        arithmetic mean (standard deviation)
    155.9 ± 19.89
    153.3 ± 19.46
    157.9 ± 24.65
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG QRS

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    End point title
    12-lead ECG QRS
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.3.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: msec
        arithmetic mean (standard deviation)
    91.1 ± 10.4
    92.4 ± 9.96
    91.4 ± 9.81
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG QT

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    End point title
    12-lead ECG QT
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.4.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: msec
        arithmetic mean (standard deviation)
    387.1 ± 25.61
    383.4 ± 25.29
    385.7 ± 26.75
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG QTcB

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    End point title
    12-lead ECG QTcB
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.5.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: msec
        arithmetic mean (standard deviation)
    427.5 ± 18.06
    428.7 ± 15.91
    427.4 ± 18.25
    No statistical analyses for this end point

    Other pre-specified: 12-lead ECG QTcF

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    End point title
    12-lead ECG QTcF
    End point description
    Triplicate serial 12-lead ECG was performed after 10 min in supine position at: pre-dose, 30 min, 1, 2, 3, 6, 8 and 10 hrs post-dose on Day 1 and Day 28. Single 12-lead ECG was performed at screening while triplicate 12-lead ECG was performed after 10 min in supine position at pre-dose on Day 9, 21, 24 of each Period. Only data from 10 hours post-dose measurement at Day 28 are reported here (see table 14.3.7.6.1 of CSR).
    End point type
    Other pre-specified
    End point timeframe
    At Day 1, Day 9, Day 21, Day 24 and Day 28
    End point values
    Test treatment - Safety population Reference treatment - Safety population Placebo - Safety population
    Number of subjects analysed
    42
    49
    43
    Units: msec
        arithmetic mean (standard deviation)
    413.3 ± 14.05
    412.8 ± 14.24
    412.8 ± 15.65
    No statistical analyses for this end point

    Other pre-specified: AUC0-t,ss of CHF6001

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    End point title
    AUC0-t,ss of CHF6001
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    38
    Units: pg*h/ml
        geometric mean (geometric coefficient of variation)
    16954 ± 42.1
    No statistical analyses for this end point

    Other pre-specified: AUC0-t,ss of CHF5956

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    End point title
    AUC0-t,ss of CHF5956
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    39
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    1097 ± 78.9
    No statistical analyses for this end point

    Other pre-specified: AUC0-t,ss of CHF6095

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    End point title
    AUC0-t,ss of CHF6095
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    39
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    322 ± 61.3
    No statistical analyses for this end point

    Other pre-specified: AUC0-24h,ss of CHF6001

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    End point title
    AUC0-24h,ss of CHF6001
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    33
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    17344 ± 39.1
    No statistical analyses for this end point

    Other pre-specified: AUC0-24h,ss of CHF5956

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    End point title
    AUC0-24h,ss of CHF5956
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    34
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    1193 ± 63.2
    No statistical analyses for this end point

    Other pre-specified: AUC0-24h,ss of CHF6095

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    End point title
    AUC0-24h,ss of CHF6095
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    27
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    374 ± 49
    No statistical analyses for this end point

    Other pre-specified: Cmin,ss of CHF6001

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    End point title
    Cmin,ss of CHF6001
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    38
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    486 ± 48.4
    No statistical analyses for this end point

    Other pre-specified: Cmax,ss of CHF6001

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    End point title
    Cmax,ss of CHF6001
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    38
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    1204 ± 35.4
    No statistical analyses for this end point

    Other pre-specified: Cmax,ss of CHF5956

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    End point title
    Cmax,ss of CHF5956
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    39
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    130 ± 60.1
    No statistical analyses for this end point

    Other pre-specified: Cmax,ss of CHF6095

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    End point title
    Cmax,ss of CHF6095
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    39
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    49.4 ± 45.4
    No statistical analyses for this end point

    Other pre-specified: Cav,ss of CHF6001

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    End point title
    Cav,ss of CHF6001
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    33
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    723 ± 39.1
    No statistical analyses for this end point

    Other pre-specified: Cav,ss of CHF5956

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    End point title
    Cav,ss of CHF5956
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    34
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    49.7 ± 63.2
    No statistical analyses for this end point

    Other pre-specified: Cav,ss of CHF6095

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    End point title
    Cav,ss of CHF6095
    End point description
    PK blood collection will be performed on Day 28 at pre-dose and at 15, 30, min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs postdose (on Day 29) of each study Period.
    End point type
    Other pre-specified
    End point timeframe
    At Day 28
    End point values
    Test treatment - PK population
    Number of subjects analysed
    27
    Units: pg/mL</