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    Clinical Trial Results:
    A Randomised, Double-Blind, Double-Dummy, Placebo-Controlled, Three-Way Cross-over Study to evaluate the effect of AF-219 on methacholine hyper-reactivity in subjects with asthma.

    Summary
    EudraCT number
    		 2013-003566-13
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2014

    Results information
    Results version number
    		 v1
    This version publication date
    30 Dec 2016
    First version publication date
    30 Dec 2016
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AF219-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01993329
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Afferent Pharmaceuticals, Inc.
    Sponsor organisation address
    2929 Campus Drive, Suite 230, San Mateo, United States, 94403
    Public contact
    Chief Medical Officer, Afferent Pharmaceuticals, Inc., 00 +1 650 286 1276, info@afferentpharma.com
    Scientific contact
    Chief Medical Officer, Afferent Pharmaceuticals, Inc., 00 +1 650 286 1276, info@afferentpharma.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
    28 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the PC20 response (concentration of methacholine required to cause at least a 20% fall in lung function) of two dose levels of AF-219 compared with placebo in subjects with asthma after provocation with methacholine.
    Protection of trial subjects
    The following stopping criteria were put in place to protect trial subjects: Diagnosis of nephro/urolithiasis, hydronephrosis; A reduction in estimated glomerular filtration rate (eGFR) by 30% or more from baseline. If the decrease of 30% or more was confirmed, the subject was withdrawn; Any severe renal/urinary adverse event (AE) (including, but not limited to, urinary retention, urinary frequency, urinary incontinence, dysuria, gross hematuria, pyelonephritis); Any clinically significant and potentially drug related progression of a rash, including increasing extent on body, rash accompanied by systemic findings (e.g., fever, lymphadenopathy) or laboratory findings (e.g., eosinophilia) or any signs or symptoms suggestive of drug-induced hypersensitivity syndrome (DiHS), also called drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome or toxic epidermal necrolysis; A confirmed pregnancy or, in the case of a male subject, his female partner became pregnant; Asthma exacerbation or respiratory tract infection requiring treatment with antibiotics; Pre-bronchodilator (after abstaining from Short acting β2-agonist for ≥8 hrs) pre-dose Forced Expiratory Volume (FEV1) on Day 1 of either Treatment Period 2 or Treatment Period 3 of less than 70% of the predicted normal value AND not within +/- 12% of the screening FEV1.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The recruitment period extended from 13 December 2013 through 06 January 2014.

    Pre-assignment
    Screening details
    		 40 subjects screened / 20 subjects enrolled. Screen failures due to (9) subjects not meeting the requirement for a positive response to the methacholine or ATP challenges, (4) subjects not meeting the FEV1 requirements, (3) subjects having abnormal ECGs, (3) subjects having abnormal lab results, and (1) subject having abnormal blood pressure.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 50 mg, AF-219 300 mg, Placebo
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days in Treatment Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Arm title
    		 AF-219 50 mg, Placebo, AF-219 300 mg
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days in Treatment Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered twice daily

    Arm title
    		 AF-219 300 mg, AF-219 50 mg, Placebo
    Arm description
    		 Participants were treatment with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 300 mg, Placebo, AF-219 50 mg
    Arm description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg for 3.5 days during Treatment Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg BID administered orally twice daily

    Arm title
    		 Placebo, AF-219 50 mg, AF-219 300 mg
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 Placebo, AF-219 300 mg, AF-219 50 mg
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet to match AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one placebo tablet to match AF-219 50 mg administered orally twice daily

    Number of subjects in period 1
    		AF-219 50 mg, AF-219 300 mg, Placebo AF-219 50 mg, Placebo, AF-219 300 mg AF-219 300 mg, AF-219 50 mg, Placebo AF-219 300 mg, Placebo, AF-219 50 mg Placebo, AF-219 50 mg, AF-219 300 mg Placebo, AF-219 300 mg, AF-219 50 mg
    Started
    3
    4
    3
    3
    3
    4
    Completed
    3
    4
    3
    3
    3
    4
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 50 mg, AF-219 300 mg, Placebo
    Arm description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 50 mg, Placebo, AF-219 300 mg
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 2.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 300 mg, AF-219 50 mg, Placebo
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 g BID for 3.5 days in Treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Arm title
    		 AF-219 300 mg, Placebo, AF-219 50 mg
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 2.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 Placebo, AF-219 50 mg, AF-219 300 mg
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Arm title
    		 Placebo, AF-219 300 mg, AF-219 50 mg
    Arm description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Number of subjects in period 2
    		AF-219 50 mg, AF-219 300 mg, Placebo AF-219 50 mg, Placebo, AF-219 300 mg AF-219 300 mg, AF-219 50 mg, Placebo AF-219 300 mg, Placebo, AF-219 50 mg Placebo, AF-219 50 mg, AF-219 300 mg Placebo, AF-219 300 mg, AF-219 50 mg
    Started
    3
    4
    3
    3
    3
    4
    Completed
    3
    3
    3
    3
    3
    3
    Not completed
    0
    1
    0
    0
    0
    1
         Personal reasons
    -
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    1
    Period 3
    Period 3 title
    Treatment Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 50 mg, AF-219 300 mg, Placebo
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 50 mg, Placebo, AF-219 300 mg
    Arm description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 300 mg, AF-219 50 mg, Placebo
    Arm description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One matching placebo tablet for AF-219 300 mg administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 AF-219 300 mg, Placebo, AF-219 50 mg
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Arm title
    		 Placebo, AF-219 50 mg, AF-219 300 mg
    Arm description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 300 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 50 mg administered orally twice daily

    Arm title
    		 Placebo, AF-219 300 mg, AF-219 50 mg
    Arm description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one AF-219 50 mg tablet administered orally twice daily

    Investigational medicinal product name
    Placebo to match AF-219 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one matching placebo tablet for AF-219 300 mg administered orally twice daily

    Number of subjects in period 3
    		AF-219 50 mg, AF-219 300 mg, Placebo AF-219 50 mg, Placebo, AF-219 300 mg AF-219 300 mg, AF-219 50 mg, Placebo AF-219 300 mg, Placebo, AF-219 50 mg Placebo, AF-219 50 mg, AF-219 300 mg Placebo, AF-219 300 mg, AF-219 50 mg
    Started
    3
    3
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1 Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 13 13
    Race
    Units: Subjects
        White
    		 20 20

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    AF-219 50 mg, AF-219 300 mg, Placebo
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days in Treatment Period 1.

    Reporting group title
    AF-219 50 mg, Placebo, AF-219 300 mg
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days in Treatment Period 1.

    Reporting group title
    AF-219 300 mg, AF-219 50 mg, Placebo
    Reporting group description
    		 Participants were treatment with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 1.

    Reporting group title
    AF-219 300 mg, Placebo, AF-219 50 mg
    Reporting group description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg for 3.5 days during Treatment Period 1.

    Reporting group title
    Placebo, AF-219 50 mg, AF-219 300 mg
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 1.

    Reporting group title
    Placebo, AF-219 300 mg, AF-219 50 mg
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 1.
    Reporting group title
    AF-219 50 mg, AF-219 300 mg, Placebo
    Reporting group description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 2.

    Reporting group title
    AF-219 50 mg, Placebo, AF-219 300 mg
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 2.

    Reporting group title
    AF-219 300 mg, AF-219 50 mg, Placebo
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 g BID for 3.5 days in Treatment Period 2.

    Reporting group title
    AF-219 300 mg, Placebo, AF-219 50 mg
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 2.

    Reporting group title
    Placebo, AF-219 50 mg, AF-219 300 mg
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 2.

    Reporting group title
    Placebo, AF-219 300 mg, AF-219 50 mg
    Reporting group description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 2.
    Reporting group title
    AF-219 50 mg, AF-219 300 mg, Placebo
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.

    Reporting group title
    AF-219 50 mg, Placebo, AF-219 300 mg
    Reporting group description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.

    Reporting group title
    AF-219 300 mg, AF-219 50 mg, Placebo
    Reporting group description
    		 Participants were treated with Placebo to match AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days in Treatment Period 3.

    Reporting group title
    AF-219 300 mg, Placebo, AF-219 50 mg
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 3.

    Reporting group title
    Placebo, AF-219 50 mg, AF-219 300 mg
    Reporting group description
    		 Participants were treated with AF-219 300 mg BID and Placebo to match AF-219 50 mg BID for 3.5 days during Treatment Period 3.

    Reporting group title
    Placebo, AF-219 300 mg, AF-219 50 mg
    Reporting group description
    		 Participants were treated with AF-219 50 mg BID and Placebo to match AF-219 300 mg BID for 3.5 days during Treatment Period 3.

    Subject analysis set title
    AF-219 50 mg BID
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants received one AF-219 50 mg tablet twice daily during one of three treatment periods

    Subject analysis set title
    AF-219 300 mg BID
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants received one AF-219 300 mg tablet twice daily during one of three treatment periods

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants received one placebo tablet twice daily during one of three treatment periods

    Primary: PC20 Methacholine Challenge

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    End point title
    		 PC20 Methacholine Challenge
    End point description
    the primary endpoint is the concentration of methacholine causing a change in FEV1 of 20% (PC20)
    End point type
    Primary
    End point timeframe
    3.5 days
    End point values
    		 AF-219 50 mg BID AF-219 300 mg BID Placebo
    Number of subjects analysed
    19
    18
    20
    Units: mg/mL
        arithmetic mean (standard deviation)
    1.66 ± 1.81
    1.31 ± 1.36
    1.87 ± 3.27
    Statistical analysis title
    		 PC20 Methacholine Challenge
    Statistical analysis description
    An ANOVA model for crossover trials including treatment and period as fixed effects and subject as a random effect were performed. P-value of fixed effects was provided. Superiority was demonstrated if the lower confidence limit of the 95% CI of the ratio of the adjusted geometric means (AF-219 300 mg vs placebo) was >1. The other treatment comparisons (AF-219 50 mg vs placebo and the one involving the two AF-219 doses) were also investigated.
    Comparison groups
    AF-219 50 mg BID v AF-219 300 mg BID v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 1
         upper limit
    		 -

    Secondary: PC20 ATP Challenge

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    End point title
    		 PC20 ATP Challenge
    End point description
    the secondary endpoint is the concentration of ATP causing a change in FEV1 of 20% (PC20)
    End point type
    Secondary
    End point timeframe
    3.5 days
    End point values
    		 AF-219 50 mg BID AF-219 300 mg BID Placebo
    Number of subjects analysed
    19
    18
    20
    Units: mg/mL
        arithmetic mean (standard deviation)
    48.52 ± 54.74
    59.19 ± 119.32
    29.11 ± 24.84
    Statistical analysis title
    		 PC20 ATP Challenge
    Statistical analysis description
    An ANOVA model for crossover trials including treatment and period as fixed effects and subject as a random effect were performed. P-value of fixed effects was provided. Superiority was demonstrated if the lower confidence limit of the 95% CI of the ratio of the adjusted geometric means (AF-219 300 mg vs placebo) was >1. Other treatment comparisons (AF-219 50 mg vs placebo and the one involving the two AF-219 doses) were also investigated.
    Comparison groups
    AF-219 50 mg BID v AF-219 300 mg BID v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 1
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through the follow-up period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    AF-219 50 mg BID
    Reporting group description
    		 -

    Reporting group title
    AF-219 300 mg BID
    Reporting group description
    		 -

    Reporting group title
    Placebo to match AF-219
    Reporting group description
    		 -

    Serious adverse events
    		 AF-219 50 mg BID AF-219 300 mg BID Placebo to match AF-219
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AF-219 50 mg BID AF-219 300 mg BID Placebo to match AF-219
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 19 (84.21%)
    19 / 19 (100.00%)
    11 / 20 (55.00%)
    Injury, poisoning and procedural complications
    contusion
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    soft tissue injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    dysgeusia
         subjects affected / exposed
    13 / 19 (68.42%)
    18 / 19 (94.74%)
    0 / 20 (0.00%)
         occurrences all number
    13
    18
    0
    hypogeusia
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    1
    migraine with aura
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    8 / 19 (42.11%)
    6 / 19 (31.58%)
    6 / 20 (30.00%)
         occurrences all number
    9
    6
    6
    General disorders and administration site conditions
    thirst
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorders
    abdominal pain lower
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    irritable bowel syndrome
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    nausea
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 19 (15.79%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    1
    Respiratory, thoracic and mediastinal disorders
    cough
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    oropharyngeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    rhinorrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    eczema
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    macule
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    anxiety
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    nocturia
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    flank pain
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    musculoskeletal discomfort
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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

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

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