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    Clinical Trial Results:
    A Study to Assess the Effect of AF-219 on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects

    Summary
    EudraCT number
    		 2015-000464-34
    Trial protocol
    		 GB  
    Global end of trial date
    16 May 2016

    Results information
    Results version number
    		 v1
    This version publication date
    31 May 2017
    First version publication date
    31 May 2017
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7264-015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02397460
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    16 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of single doses of AF-219 300 mg (Cohort 1) and 50 mg (Cohort 2) on cough reflex sensitivity to capsaicin in both healthy and chronic cough subjects.
    Protection of trial subjects
    The Investigators agreed to conduct the study in compliance with the study Protocol, with the International Standard of Good Clinical Practice (GCP) procedures, with all applicable local GCP standards and regulations, and with the principles of the Declaration of Helsinki (1964) and relevant amendments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Apr 2015
    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: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    42
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The main purpose of the 14-day Screening period (Day -14 to Day -1) was to ensure that each participant met all the specified eligibility criteria. In addition, cough sensitivity was measured at Screening by standard clinical methodology using cough challenge in response to capsaicin.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 300 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 300 mg (6 x 50 mg), administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 300 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 50 mg, administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 50 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		AF-219 300 mg/Healthy (Sequence A) AF-219 300 mg /Healthy (Sequence B) AF-219 300 mg/Chronic Cough (Sequence A) AF-219 300 mg/Chronic Cough (Sequence B) AF-219 50 mg/Healthy (Sequence A) AF-219 50 mg /Healthy (Sequence B) AF-219 50 mg/Chronic Cough (Sequence A) AF-219 50 mg/Chronic Cough (Sequence B)
    Started
    7
    7
    6
    6
    6
    6
    6
    6
    Completed
    7
    7
    6
    6
    6
    6
    6
    6
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 300 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 300 mg (6 x 50 mg), administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 300 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 50 mg, administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 50 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		AF-219 300 mg/Healthy (Sequence A) AF-219 300 mg /Healthy (Sequence B) AF-219 300 mg/Chronic Cough (Sequence A) AF-219 300 mg/Chronic Cough (Sequence B) AF-219 50 mg/Healthy (Sequence A) AF-219 50 mg /Healthy (Sequence B) AF-219 50 mg/Chronic Cough (Sequence A) AF-219 50 mg/Chronic Cough (Sequence B)
    Started
    7
    7
    6
    6
    6
    6
    6
    6
    Completed
    7
    7
    6
    6
    6
    6
    6
    5
    Not completed
    0
    0
    0
    0
    0
    0
    0
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 300 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 300 mg (6 x 50 mg), administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 300 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 50 mg, administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 50 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		AF-219 300 mg/Healthy (Sequence A) AF-219 300 mg /Healthy (Sequence B) AF-219 300 mg/Chronic Cough (Sequence A) AF-219 300 mg/Chronic Cough (Sequence B) AF-219 50 mg/Healthy (Sequence A) AF-219 50 mg /Healthy (Sequence B) AF-219 50 mg/Chronic Cough (Sequence A) AF-219 50 mg/Chronic Cough (Sequence B)
    Started
    7
    7
    6
    6
    6
    6
    6
    5
    Completed
    7
    7
    6
    6
    6
    6
    6
    5
    Period 4
    Period 4 title
    Treatment Period 4
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AF-219 300 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 300 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 300 mg (6 x 50 mg), administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 300 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 300 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 300 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    AF-219 50 mg
    Investigational medicinal product code
    AF-219
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AF-219 50 mg, administered as a single dose, with crossover to/from placebo in treatment Period 1 through treatment Period 4

    Arm title
    		 AF-219 50 mg /Healthy (Sequence B)
    Arm description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence A)
    Arm description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 AF-219 50 mg/Chronic Cough (Sequence B)
    Arm description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Arm type
    		 AF-219 50 mg in Pd. 1 & 3, placebo in Pd. 2 & 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		AF-219 300 mg/Healthy (Sequence A) AF-219 300 mg /Healthy (Sequence B) AF-219 300 mg/Chronic Cough (Sequence A) AF-219 300 mg/Chronic Cough (Sequence B) AF-219 50 mg/Healthy (Sequence A) AF-219 50 mg /Healthy (Sequence B) AF-219 50 mg/Chronic Cough (Sequence A) AF-219 50 mg/Chronic Cough (Sequence B)
    Started
    7
    7
    6
    6
    6
    5
    6
    6
    Completed
    7
    6
    6
    6
    5
    5
    6
    6
    Not completed
    0
    1
    0
    0
    1
    0
    0
    0
         Physician decision
    -
    -
    -
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
    -
    -
    -
    -

    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
    		 50 50
    Age Categorical
    Participants who received AF-219 300 mg (Cohort 1), AF-219 50 mg (Cohort 2), or placebo (Cohorts 1 and 2)
    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)
    		 42 42
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Age Continuous
    Healthy participants who received AF-219 300 mg (Cohort 1), AF-219 50 mg (Cohort 2), or placebo (Cohorts 1 and 2)
    Units: years
        arithmetic mean (standard deviation)
    		 42.7 ( 14.2 ) -
    Gender Categorical
    Healthy participants who received AF-219 300 mg (Cohort 1), AF-219 50 mg (Cohort 2), or placebo (Cohorts 1 and 2)
    Units: Subjects
        Female
    		 19 19
        Male
    		 31 31

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    AF-219 300 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Reporting group title
    AF-219 300 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Reporting group title
    AF-219 300 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4
    Reporting group title
    AF-219 300 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 300 mg in Periods 1 & 3

    Reporting group title
    AF-219 300 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 300 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg /Healthy (Sequence B)
    Reporting group description
    		 Healthy participants received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Participants with chronic cough received placebo, had a 2-week washout, and then switched to AF-219 50 mg in Periods 1 & 3

    Reporting group title
    AF-219 50 mg/Chronic Cough (Sequence B)
    Reporting group description
    		 Participants with chronic cough received AF-219 50 mg, had a 2-week washout, and then switched to placebo in Periods 2 & 4

    Subject analysis set title
    Healthy Males, Placebo: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males who received placebo and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough Males, Placebo: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males with chronic cough who received placebo and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough Females, Placebo: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Females with chronic cough who received placebo and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy Males, AF-219: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males who received AF-219 (300 mg or 50 mg) and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough Males, AF-219: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males with chronic cough who received AF-219 (300 mg or 50 mg) and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough Females, AF-219: Capsaicin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Females with chronic cough who received AF-219 (300 mg or 50 mg) and had capsaicin-evoked cough challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy Males, Placebo: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males who received placebo and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy Males, AF-219 50 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males who received AF-219 50 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Males, Placebo: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males with chronic cough who received placebo and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Males, AF-219 50 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males with chronic cough who received AF-219 50 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Females, Placebo: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Females with chronic cough who received placebo and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Females, AF-219 50 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Females with chronic cough who received AF-219 50 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy Males, AF-219 300 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males who received AF-219 300 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Males, AF-219 300 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males with chronic cough who received AF-219 300 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough Females, AF-219 300 mg: ATP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Females with chronic cough who received AF-219 300 mg and had ATP-evoked cough challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/AF-219 300 mg: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 300 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/Placebo: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 1 who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/AF-219 300 mg: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 300 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/Placebo: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 1 with chronic cough who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/AF-219 50 mg: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 50 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/Placebo: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 2 who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/AF-219 50 mg: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 50 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/Placebo: Capsaicin (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough in Cohort 2 who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/AF-219 300 mg: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 300 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/Placebo: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 1 who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/AF-219 300 mg: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 300 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/Placebo: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 1 with chronic cough who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/AF-219 50 mg: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 50 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/Placebo: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 2 who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/AF-219 50 mg: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 50 mg and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Chronic Cough/Placebo: Capsaicin (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 2 with chronic cough who received placebo and had capsaicin challenge 2 hours post-dose in Periods 1 & 2

    Subject analysis set title
    Healthy/AF-219 300 mg: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 300 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/Placebo: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 1 who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/AF-219 300 mg: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 300 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/Placebo: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 1 with chronic cough who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/AF-219 50 mg: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 50 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/Placebo: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 2 who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/AF-219 50 mg: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 50 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/Placebo: ATP (C2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough in Cohort 2 who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/AF-219 300 mg: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 300 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/Placebo: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 1 who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/AF-219 300 mg: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 300 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/Placebo: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 1 with chronic cough who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/AF-219 50 mg: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females who received AF-219 50 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Healthy/Placebo: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy males and females in Cohort 2 who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/AF-219 50 mg: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females with chronic cough who received AF-219 50 mg and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    Chronic Cough/Placebo: ATP (C5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Males and females in Cohort 2 with chronic cough who received placebo and had ATP challenge 2 hours post-dose in Periods 3 & 4

    Subject analysis set title
    AF-219 300 mg Cough: Capsaicin (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (AF-219 300 mg) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: Capsaicin (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (placebo) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    AF-219 300 mg Cough: Capsaicin (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (AF-219 300 mg) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: Capsaicin (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (placebo) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    AF-219 50 mg Cough: Capsaicin (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (AF-219 50 mg) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: Capsaicin (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (Placebo) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    AF-219 50 mg Cough: Capsaicin (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (AF-219 50 mg) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: Capsaicin (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (placebo) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    AF-219 300 mg Cough: ATP (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (AF-219 300 mg) who recorded their urge-to-cough on Day 1, 4 hours post-dose following ATP challenge

    Subject analysis set title
    Placebo Cough: ATP (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (Placebo) who recorded their urge-to-cough on Day 1, 4 hours post-dose following ATP challenge

    Subject analysis set title
    AF-219 300 mg Cough: ATP (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (AF-219 300 mg) who recorded their urge-to-cough on Day 2, 24 hours post-dose following ATP challenge

    Subject analysis set title
    Placebo Cough: ATP (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 1 (Placebo) who recorded their urge-to-cough on Day 2, 24 hours post-dose following ATP challenge

    Subject analysis set title
    AF-219 50 mg Cough: ATP (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (AF-219 50 mg) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: ATP (Day 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (Placebo) who recorded their urge-to-cough on Day 1, 4 hours post-dose following capsaicin challenge

    Subject analysis set title
    AF-219 50 mg Cough: ATP (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (AF-219 50 mg) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    Placebo Cough: ATP (Day 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants in Cohort 2 (Placebo) who recorded their urge-to-cough on Day 2, 24 hours post-dose following capsaicin challenge

    Subject analysis set title
    Healthy Participants: AF-219 300 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Healthy Participants: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Chronic Cough Participants: AF-219 300 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Chronic Cough Participants: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Healthy Participants: AF-219 50 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Healthy Participants: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Chronic Cough Participants: AF-219 50 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Chronic Cough Participants: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Subject analysis set title
    Chronic Cough Participants: Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants with adverse events

    Primary: Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax) in Healthy and Chronic Cough Participants (Males and Females)

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    End point title
    		 Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax) in Healthy and Chronic Cough Participants (Males and Females)
    End point description
    A co-primary objective was to assess the effect of single doses of 300 mg and 50 mg AF-219 on cough reflex sensitivity to challenge with capsaicin in both healthy participants and participants with chronic cough. Capsaicin-evoked cough challenge was performed 2 hours post-dose in Periods 1 & 2. The maximal cough response (Emax) to capsaicin was assessed. For capsaicin challenge doubling concentrations from 0.49-1000 μM were prepared by dilution of stock solutions with saline. The number of explosive cough sounds occurring within the first 15 seconds after inhalation are recorded. Nonlinear mixed-effects modeling was used to estimate the Emax. Population pharmacodynamic modelling was performed in NONMEM 7.3. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of Emax in response to capsaicin challenge.
    End point type
    Primary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy Males, Placebo: Capsaicin Chronic Cough Males, Placebo: Capsaicin Chronic Cough Females, Placebo: Capsaicin Healthy Males, AF-219: Capsaicin Chronic Cough Males, AF-219: Capsaicin Chronic Cough Females, AF-219: Capsaicin
    Number of subjects analysed
    14 [1]
    3
    10
    14
    3
    10
    Units: Emax (Explosive coughs/15 sec)
        number (not applicable)
    4.14
    4.14
    7.55
    3.66
    3.37
    6.15
    Notes
    [1] - All of the values presented in this table are model-based.
    Statistical analysis title
    		 Emax Response: AF-219 v Placebo
    Statistical analysis description
    Treatment effects on Emax following capsaicin challenge were modeled for dose dependence and were estimated on the basis of disease status for participants who were healthy or had chronic cough and received AF-219 300 mg, AF-219 50 mg, or placebo.
    Comparison groups
    Healthy Males, Placebo: Capsaicin v Chronic Cough Males, Placebo: Capsaicin v Chronic Cough Females, Placebo: Capsaicin v Healthy Males, AF-219: Capsaicin v Chronic Cough Males, AF-219: Capsaicin v Chronic Cough Females, AF-219: Capsaicin
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (E50) in Healthy and Chronic Cough Participants (Males and Females)

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    End point title
    		 Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (E50) in Healthy and Chronic Cough Participants (Males and Females)
    End point description
    A co-primary objective was to assess the effect of single doses of 300 mg and 50 mg AF-219 on cough reflex sensitivity to challenge with capsaicin in both healthy participants and participants with chronic cough (CC). Capsaicin-evoked cough challenge was performed 2 hours post-dose in Periods 1 & 2. The concentration of capsaicin required to induce 50% of the Emax (ED50) was assessed. For capsaicin challenge doubling concentrations from 0.49-1000 μM were prepared by dilution of stock solutions with saline. Nonlinear mixed-effects modeling was used to estimate the ED50. Population pharmacodynamic modelling was performed in NONMEM 7.3 using Laplace estimation method. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of ED50 in response to capsaicin challenge.
    End point type
    Primary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy Males, Placebo: Capsaicin Chronic Cough Males, Placebo: Capsaicin Chronic Cough Females, Placebo: Capsaicin Healthy Males, AF-219: Capsaicin Chronic Cough Males, AF-219: Capsaicin Chronic Cough Females, AF-219: Capsaicin
    Number of subjects analysed
    14 [2]
    3
    10
    14
    3
    10
    Units: µM
        number (not applicable)
    33
    33
    9.57
    33
    33
    9.57
    Notes
    [2] - All of the values presented in this table are model-based.
    Statistical analysis title
    		 ED50 Response: AF-219 v Placebo
    Statistical analysis description
    Treatment effects following capsaicin challenge were modeled for dose dependence and were estimated on the basis of disease status for participants who had chronic cough and received AF-219 300 mg, AF-219 50 mg, or placebo.
    Comparison groups
    Chronic Cough Males, Placebo: Capsaicin v Chronic Cough Females, Placebo: Capsaicin v Chronic Cough Males, AF-219: Capsaicin v Chronic Cough Females, AF-219: Capsaicin
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax) in Healthy and Chronic Cough Participants (Males and Females)

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    End point title
    		 Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax) in Healthy and Chronic Cough Participants (Males and Females)
    End point description
    A secondary objective was to assess the effect of single doses of 300 mg and 50 mg AF-219 on cough reflex sensitivity to challenge with adenosine triphosphate (ATP) in both healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 & 4. For ATP challenge doubling concentrations from 0.227 to 929 μmol/mL were prepared from ATP powder dissolved in saline. The number of explosive cough sounds occurring within the first 15 seconds after inhalation are recorded. Nonlinear mixed-effects modeling was used to estimate the Emax. Population pharmacodynamic modelling was performed in NONMEM 7.3. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of Emax in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy Males, Placebo: ATP Healthy Males, AF-219 50 mg: ATP Chronic Cough Males, Placebo: ATP Chronic Cough Males, AF-219 50 mg: ATP Chronic Cough Females, Placebo: ATP Chronic Cough Females, AF-219 50 mg: ATP Healthy Males, AF-219 300 mg: ATP Chronic Cough Males, AF-219 300 mg: ATP Chronic Cough Females, AF-219 300 mg: ATP
    Number of subjects analysed
    14 [3]
    14
    3
    3
    5
    5
    14
    3
    3
    Units: Emax (Explosive coughs/15 sec)
        number (not applicable)
    2.35
    2.35
    2.35
    2.35
    5.41
    5.41
    2.35
    2.35
    5.41
    Notes
    [3] - All of the values presented in this table are model-based.
    No statistical analyses for this end point

    Secondary: Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (E50) in Healthy and Chronic Cough Participants (Males and Females)

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    End point title
    		 Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (E50) in Healthy and Chronic Cough Participants (Males and Females)
    End point description
    A secondary objective was to assess the effect of single doses of 300 mg and 50 mg AF-219 on cough reflex sensitivity to challenge with ATP in both healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 & 4. The concentration of capsaicin required to induce 50% of the Emax (ED50) was assessed. For capsaicin challenge doubling concentrations from 0.227-929 μmol/mL were prepared by dilution of stock solutions with saline. Nonlinear mixed-effects modeling was used to estimate the ED50. Population pharmacodynamic modelling was performed in NONMEM 7.3 using Laplace estimation method. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of ED50 in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy Males, Placebo: ATP Healthy Males, AF-219 50 mg: ATP Chronic Cough Males, Placebo: ATP Chronic Cough Males, AF-219 50 mg: ATP Chronic Cough Females, Placebo: ATP Chronic Cough Females, AF-219 50 mg: ATP Healthy Males, AF-219 300 mg: ATP Chronic Cough Males, AF-219 300 mg: ATP Chronic Cough Females, AF-219 300 mg: ATP
    Number of subjects analysed
    14 [4]
    14
    3
    3
    5
    5
    14
    3
    5
    Units: µmol/mL
        number (not applicable)
    54.9
    119.13
    54.9
    155.92
    8.62
    24.48
    119.13
    192.7
    30.25
    Notes
    [4] - All of the values presented in this table are model-based.
    No statistical analyses for this end point

    Secondary: Concentrations of Capsaicin Inducing 2 or More Coughs (C2)

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    End point title
    		 Concentrations of Capsaicin Inducing 2 or More Coughs (C2)
    End point description
    The concentrations of capsaicin inducing 2 or more coughs (C2) were assessed in treatment Periods 1 & 2 combined. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of C2 in response to capsaicin challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy/AF-219 300 mg: Capsaicin (C2) Healthy/Placebo: Capsaicin (C2) Chronic Cough/AF-219 300 mg: Capsaicin (C2) Chronic Cough/Placebo: Capsaicin (C2) Healthy/AF-219 50 mg: Capsaicin (C2) Healthy/Placebo: Capsaicin (C2) Chronic Cough/AF-219 50 mg: Capsaicin (C2) Chronic Cough/Placebo: Capsaicin (C2)
    Number of subjects analysed
    12
    14
    10
    10
    12
    12
    10
    12
    Units: µM
        median (full range (min-max))
    31.25 (4 to 1000)
    31.25 (4 to 500)
    3.9 (0 to 16)
    7.81 (0 to 31)
    15.62 (2 to 63)
    23.44 (8 to 125)
    15.62 (0 to 125)
    5.86 (0 to 250)
    No statistical analyses for this end point

    Secondary: Concentrations of Capsaicin Inducing 5 or More Coughs (C5)

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    End point title
    		 Concentrations of Capsaicin Inducing 5 or More Coughs (C5)
    End point description
    The concentrations of capsaicin inducing 5 or more coughs (C5) were assessed in treatment Periods 1 & 2 combined. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of C5 in response to capsaicin challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy/AF-219 300 mg: Capsaicin (C5) Healthy/Placebo: Capsaicin (C5) Chronic Cough/AF-219 300 mg: Capsaicin (C5) Chronic Cough/Placebo: Capsaicin (C5) Healthy/AF-219 50 mg: Capsaicin (C5) Healthy/Placebo: Capsaicin (C5) Chronic Cough/AF-219 50 mg: Capsaicin (C5) Chronic Cough/Placebo: Capsaicin (C5)
    Number of subjects analysed
    5
    6
    10
    10
    6
    7
    7
    10
    Units: µM
        median (full range (min-max))
    31.25 (16 to 250)
    62.5 (16 to 1000)
    3.9 (0 to 31)
    11.72 (0 to 125)
    250 (63 to 500)
    125 (63 to 500)
    15.62 (2 to 63)
    5.86 (0 to 31)
    No statistical analyses for this end point

    Secondary: Concentrations of ATP Inducing 2 or More Coughs (C2)

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    End point title
    		 Concentrations of ATP Inducing 2 or More Coughs (C2)
    End point description
    The concentrations of ATP inducing 2 or more coughs (C2) were assessed in treatment Periods 3 & 4 combined. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of C2 in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy/AF-219 300 mg: ATP (C2) Healthy/Placebo: ATP (C2) Chronic Cough/AF-219 300 mg: ATP (C2) Chronic Cough/Placebo: ATP (C2) Healthy/AF-219 50 mg: ATP (C2) Healthy/Placebo: ATP (C2) Chronic Cough/AF-219 50 mg: ATP (C2) Chronic Cough/Placebo: ATP (C2)
    Number of subjects analysed
    10
    11
    7
    11
    9
    8
    8
    9
    Units: mg/mL
        median (full range (min-max))
    192 (8 to 256)
    64 (1 to 512)
    8 (0 to 64)
    1 (0 to 64)
    16 (8 to 256)
    24 (2 to 512)
    4.25 (0 to 512)
    4 (0 to 256)
    No statistical analyses for this end point

    Secondary: Concentrations of ATP Inducing 5 or More Coughs (C5)

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    End point title
    		 Concentrations of ATP Inducing 5 or More Coughs (C5)
    End point description
    The concentrations of ATP inducing 5 or more coughs (C5) were assessed in treatment Periods 3 & 4 combined. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of C5 in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose
    End point values
    		 Healthy/AF-219 300 mg: ATP (C5) Healthy/Placebo: ATP (C5) Chronic Cough/AF-219 300 mg: ATP (C5) Chronic Cough/Placebo: ATP (C5) Healthy/AF-219 50 mg: ATP (C5) Healthy/Placebo: ATP (C5) Chronic Cough/AF-219 50 mg: ATP (C5) Chronic Cough/Placebo: ATP (C5)
    Number of subjects analysed
    2
    5
    7
    8
    4
    4
    5
    8
    Units: mg/mL
        median (full range (min-max))
    192 (128 to 256)
    128 (64 to 256)
    8 (0 to 64)
    16.5 (0 to 512)
    64 (32 to 256)
    32 (2 to 32)
    128 (8 to 512)
    4 (0 to 128)
    No statistical analyses for this end point

    Secondary: Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants)

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    End point title
    		 Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants)
    End point description
    In response to capsaicin challenge in Periods 1 & 2 (combined), participants with chronic cough completed a visual analogue scale (VAS) at the end of each 4-hour observation period on Day 1, and 24 hours after each observation period, on Day 2. Participants used a 100mm VAS to record the severity of their urge to cough marked at the extremes as ‘No urge-to-cough’ (0 mm) and ‘Worst urge-to-cough’ (100 mm). They drew a single vertical line on the VAS to indicate how severe their urge to cough was during the previous 4 hours on Day 1 of each Treatment Period, and during the previous 24 hours (Day 2 of each Treatment Period). The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of urge-to-cough in response to capsaicin challenge.
    End point type
    Secondary
    End point timeframe
    4 hours and 24 hours post-dose
    End point values
    		 AF-219 300 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1) AF-219 300 mg Cough: Capsaicin (Day 2) Placebo Cough: Capsaicin (Day 2) AF-219 50 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1) AF-219 50 mg Cough: Capsaicin (Day 2) Placebo Cough: Capsaicin (Day 2)
    Number of subjects analysed
    12
    12
    12
    12
    12
    11
    12
    11
    Units: mm
        arithmetic mean (standard deviation)
    28.9 ( 29.79 )
    38.6 ( 26.82 )
    28.2 ( 32.72 )
    46.7 ( 29.2 )
    36.6 ( 30.84 )
    20.5 ( 11.54 )
    41.8 ( 31.02 )
    36.7 ( 23.28 )
    No statistical analyses for this end point

    Secondary: Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants)

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    End point title
    		 Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants)
    End point description
    In response to ATP challenge in Periods 3 & 4 (combined), participants with chronic cough completed a VAS at the end of each 4-hour observation period on Day 1, and 24 hours after each observation period, on Day 2. Participants used a 100mm VAS to record the severity of their urge to cough marked at the extremes as ‘No urge-to-cough’ (0 mm) and ‘Worst urge-to-cough’ (100 mm). They drew a single vertical line on the VAS to indicate how severe their urge to cough was during the previous 4 hours on Day 1 of each Treatment Period, and during the previous 24 hours (Day 2 of each Treatment Period). The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of urge-to-cough in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    4 hours and 24 hours post-dose
    End point values
    		 AF-219 300 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1) AF-219 300 mg Cough: ATP (Day 2) Placebo Cough: ATP (Day 2) AF-219 50 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1) AF-219 50 mg Cough: ATP (Day 2) Placebo Cough: ATP (Day 2)
    Number of subjects analysed
    12
    12
    12
    12
    11
    11
    11
    11
    Units: mm
        arithmetic mean (standard deviation)
    19.8 ( 23.54 )
    34.4 ( 26.78 )
    21.6 ( 20.65 )
    39.8 ( 26.51 )
    21.5 ( 22.45 )
    25.3 ( 19.69 )
    27.5 ( 29.54 )
    37.5 ( 27.33 )
    No statistical analyses for this end point

    Secondary: Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants)

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    End point title
    		 Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants)
    End point description
    In response to capsaicin challenge in Periods 1 & 2 (combined), participants with chronic cough completed a VAS at the end of each 4-hour observation period on Day 1, and 24 hours after each observation period, on Day 2. Participants used a 100mm VAS to record their cough severity marked at the extremes as ‘No Cough’ (0 mm) and ‘Worst Cough’ (100 mm). They drew a single vertical line on the VAS to indicate how severe their urge to cough was during the previous 4 hours on Day 1 of each Treatment Period, and during the previous 24 hours (Day 2 of each Treatment Period). The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of cough severity in response to capsaicin challenge.
    End point type
    Secondary
    End point timeframe
    4 hours and 24 hours post-dose
    End point values
    		 AF-219 300 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1) AF-219 300 mg Cough: Capsaicin (Day 2) Placebo Cough: Capsaicin (Day 2) AF-219 50 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1) AF-219 50 mg Cough: Capsaicin (Day 2) Placebo Cough: Capsaicin (Day 2)
    Number of subjects analysed
    12
    12
    12
    12
    12
    11
    12
    11
    Units: mm
        arithmetic mean (standard deviation)
    28.2 ( 30.71 )
    35.7 ( 24.32 )
    25.8 ( 30.2 )
    44.3 ( 27.43 )
    30.9 ( 27.22 )
    20.5 ( 12.75 )
    39.8 ( 28.97 )
    35.5 ( 22.25 )
    No statistical analyses for this end point

    Secondary: Cough Severity in Response to ATP Challenge (Chronic Cough Participants)

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    End point title
    		 Cough Severity in Response to ATP Challenge (Chronic Cough Participants)
    End point description
    In response to ATP challenge in Periods 3 & 4 (combined), participants with chronic cough completed a VAS at the end of each 4-hour observation period on Day 1, and 24 hours after each observation period, on Day 2. Participants used a 100mm VAS to record their cough severity marked at the extremes as ‘No Cough’ (0 mm) and ‘Worst Cough’ (100 mm). They drew a single vertical line on the VAS to indicate how severe their urge to cough was during the previous 4 hours on Day 1 of each Treatment Period, and during the previous 24 hours (Day 2 of each Treatment Period). The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of cough severity in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    4 hours and 24 hours post-dose
    End point values
    		 AF-219 300 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1) AF-219 300 mg Cough: ATP (Day 2) Placebo Cough: ATP (Day 2) AF-219 50 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1) AF-219 50 mg Cough: ATP (Day 2) Placebo Cough: ATP (Day 2)
    Number of subjects analysed
    12
    12
    12
    12
    11
    11
    11
    11
    Units: mm
        arithmetic mean (standard deviation)
    21.5 ( 27.06 )
    32.7 ( 24.23 )
    18.9 ( 18.29 )
    36.8 ( 26.5 )
    21.2 ( 21.04 )
    23.5 ( 16.02 )
    27.5 ( 26.78 )
    35.5 ( 24.07 )
    No statistical analyses for this end point

    Secondary: Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge

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    End point title
    		 Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge
    End point description
    Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant’s clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of capsaicin challenge to bedtime on Day 1 in treatment Periods 1 & 2. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of daytime cough frequency in response to capsaicin challenge.
    End point type
    Secondary
    End point timeframe
    From start of challenge (2 hours post-dose) to bedtime; Up to 12 hours
    End point values
    		 AF-219 300 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1) AF-219 50 mg Cough: Capsaicin (Day 1) Placebo Cough: Capsaicin (Day 1)
    Number of subjects analysed
    12
    12
    12
    12
    Units: coughs/hour
        arithmetic mean (standard deviation)
    13.7 ( 13.85 )
    19.1 ( 16.76 )
    15.5 ( 16.92 )
    20.3 ( 13.27 )
    No statistical analyses for this end point

    Secondary: Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge

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    End point title
    		 Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge
    End point description
    Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant’s clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of ATP challenge to bedtime on Day 1 in treatment Periods 3 & 4. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour. The analysed population was all treated participants who had at least 1 post-dose secondary endpoint assessment of daytime cough frequency in response to ATP challenge.
    End point type
    Secondary
    End point timeframe
    From start of challenge (2 hours post-dose) to bedtime; Up to 12 hours
    End point values
    		 AF-219 300 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1) AF-219 50 mg Cough: ATP (Day 1) Placebo Cough: ATP (Day 1)
    Number of subjects analysed
    12
    12
    11
    11
    Units: coughs/hour
        arithmetic mean (standard deviation)
    10.3 ( 11.65 )
    22.3 ( 15.48 )
    15.6 ( 17.31 )
    26.4 ( 16.75 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced at Least One Adverse Event (AE) During Treatment and Post-treatment Follow-up

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    End point title
    		 Percentage of Participants Who Experienced at Least One Adverse Event (AE) During Treatment and Post-treatment Follow-up
    End point description
    A secondary endpoint of the trial was the percentage of participants receiving MK-7264 at any dose (300 mg or 50 mg) who had at least 1 AE over 24 days of treatment (including washout periods) in addition to 14 days (+3 days) until a post-treatment follow-up visit. The relative number (n/N [%]) of participants in any treatment group with at least 1 AE was assessed for days 1-41. The analysed population was all randomized participants who took at least 1 dose of study treatment and had assessment of AE occurrence.
    End point type
    Secondary
    End point timeframe
    Up to Day 41
    End point values
    		 Healthy Participants: AF-219 300 mg Healthy Participants: Placebo Chronic Cough Participants: AF-219 300 mg Chronic Cough Participants: Placebo Healthy Participants: AF-219 50 mg Healthy Participants: Placebo Chronic Cough Participants: AF-219 50 mg Chronic Cough Participants: Placebo
    Number of subjects analysed
    14
    14
    12
    12
    12
    12
    12
    11
    Units: Percentage of Participants
        number (not applicable)
    100
    35.7
    100
    58.3
    75
    33.3
    50
    27.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
    End point description
    A secondary endpoint of the trial was the percentage of participants receiving MK-7264 at any dose (300 mg or 50 mg) who discontinued treatment due to an AE. The relative number (n/N [%]) of participants who discontinued treatment due to AEs was assessed for days 1-24. The analysed population was all randomized participants who took at least 1 dose of study treatment and had assessment of discontinuation due to an AE.
    End point type
    Secondary
    End point timeframe
    Up to Day 24
    End point values
    		 Healthy Participants: AF-219 300 mg Chronic Cough Participants: AF-219 300 mg Healthy Participants: AF-219 50 mg Chronic Cough Participants: AF-219 50 mg
    Number of subjects analysed
    14
    12
    12
    12
    Units: Percentage of participants
        number (not applicable)
    7.1
    0
    8.3
    8.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 41
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Cohort 1-Healthy Subjects: AF-219 300 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 1-Healthy Subjects: Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 1-Chronic Cough Subjects: AF-219 300 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 1-Chronic Cough Subjects: Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 2-Healthy Subjects: AF-219 50 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 2-Healthy Subjects: Placebo
    Reporting group description
    		 -

    Reporting group title
    Cohort 2-Chronic Cough Subjects: AF-219 50 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 2-Chronic Cough Subjects: Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1-Healthy Subjects: AF-219 300 mg Cohort 1-Healthy Subjects: Placebo Cohort 1-Chronic Cough Subjects: AF-219 300 mg Cohort 1-Chronic Cough Subjects: Placebo Cohort 2-Healthy Subjects: AF-219 50 mg Cohort 2-Healthy Subjects: Placebo Cohort 2-Chronic Cough Subjects: AF-219 50 mg Cohort 2-Chronic Cough Subjects: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1-Healthy Subjects: AF-219 300 mg Cohort 1-Healthy Subjects: Placebo Cohort 1-Chronic Cough Subjects: AF-219 300 mg Cohort 1-Chronic Cough Subjects: Placebo Cohort 2-Healthy Subjects: AF-219 50 mg Cohort 2-Healthy Subjects: Placebo Cohort 2-Chronic Cough Subjects: AF-219 50 mg Cohort 2-Chronic Cough Subjects: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    5 / 14 (35.71%)
    12 / 12 (100.00%)
    7 / 12 (58.33%)
    9 / 12 (75.00%)
    4 / 12 (33.33%)
    6 / 12 (50.00%)
    3 / 11 (27.27%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Excoriation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
    4 / 12 (33.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    0
    4
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    13 / 14 (92.86%)
    1 / 14 (7.14%)
    9 / 12 (75.00%)
    1 / 12 (8.33%)
    4 / 12 (33.33%)
    0 / 12 (0.00%)
    3 / 12 (25.00%)
    1 / 11 (9.09%)
         occurrences all number
    20
    1
    15
    1
    5
    0
    5
    1
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 14 (14.29%)
    5 / 12 (41.67%)
    2 / 12 (16.67%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
         occurrences all number
    3
    2
    5
    2
    2
    1
    1
    2
    Hypogeusia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    3
    0
    2
    0
    1
    0
    VIIth Nerve Paralysis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Dry mouth
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    4 / 14 (28.57%)
    0 / 14 (0.00%)
    4 / 12 (33.33%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    4
    1
    0
    0
    1
    0
    Reflux gastritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Tongue coated
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Tooth deposit
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
    3 / 12 (25.00%)
    3 / 12 (25.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    3
    3
    0
    Dry throat
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Pharyngeal hypoaesthesia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    1
    0
    1
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2015
    Added steps specifying when and for which treatment group the cough monitor was attached and removed
    17 Jul 2015
    Clarified that an ambulatory cough recorder chest microphone (in addition to the lapel microphone) would be used for cough participants only
    05 Aug 2015
    Removed spirometry from the Schedule of Assessments and Procedures
    02 Sep 2015
    Low Dose Extension (AF-219 50 mg, Cohort 2) added to include up to an additional 24 participants
    19 Oct 2015
    Time frame of the exclusion criteria for treatment with an investigational drug decreased to facilitate the enrollment of participants in Cohort 1 into Cohort 2

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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