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    Clinical Trial Results:
    A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects with Refractory Chronic Cough

    Summary
    EudraCT number
    		 2015-000474-35
    Trial protocol
    		 GB  
    Global end of trial date
    09 Feb 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Dec 2020
    First version publication date
    30 Jul 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated for Consistency with ClinicalTrials.gov Results posting

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7264-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02349425
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck study number: MK-7264-010, Afferent study number: AF219-010
    Sponsors
    Sponsor organisation name
    Afferent Pharmaceuticals, Inc.
    Sponsor organisation address
    2929 Campus Dr #230, San Mateo, CA, United States, 94403
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., 1 8006726372, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Senior Vice President, Global Clinical Development, Merck Sharp & Dohme Corp., 1 8006726372, 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
    09 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the dose-response of Gefapixant (AF-219) in reducing Awake Objective Cough Frequency and to identify tolerable dose(s) of Gefapixant that reduce Awake Objective Cough Frequency.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Mar 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 States: 59
    Worldwide total number of subjects
    59
    EEA total number of subjects
    0
    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)
    31
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited at 12 clinical trial sites in the United States.

    Pre-assignment
    Screening details
    		 29 participants were enrolled, randomized and treated with study drug in Cohort 1 and 30 participants in Cohort 2. Of the 30 participants in Cohort 2, 18 of them were from Cohort 1 and they re-consented, were given new randomization numbers and treated with study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Gefapixant>Placebo
    Arm description
    		 Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 50 mg, 100 mg, 150 mg, or 200 mg oral, administered as 1, 2, 3, or 4 50-mg tablets BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Arm title
    		 Cohort 1: Placebo>Gefapixant
    Arm description
    		 Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 50 mg, 100 mg, 150 mg, or 200 mg oral, administered as 1, 2, 3, or 4 50-mg tablets BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Arm title
    		 Cohort 2: Gefapixant>Placebo
    Arm description
    		 Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 7.5 mg, 15 mg, 30 mg, or 50 mg oral, administered as 1, 2, or 4 7.5-mg tablets or 1 50-mg tablet BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Arm title
    		 Cohort 2: Placebo>Gefapixant
    Arm description
    		 Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 7.5 mg, 15 mg, 30 mg, or 50 mg oral, administered as 1, 2, or 4 7.5-mg tablets or 1 50-mg tablet BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Number of subjects in period 1
    		Cohort 1: Gefapixant>Placebo Cohort 1: Placebo>Gefapixant Cohort 2: Gefapixant>Placebo Cohort 2: Placebo>Gefapixant
    Started
    15
    14
    15
    15
    Completed
    14
    13
    15
    15
    Not completed
    1
    1
    0
    0
         Adverse event, non-fatal
    1
    1
    -
    -
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Gefapixant>Placebo
    Arm description
    		 Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 50 mg, 100 mg, 150 mg, or 200 mg oral, administered as 1, 2, 3, or 4 50-mg tablets BID for 4 days

    Arm title
    		 Cohort 1: Placebo>Gefapixant
    Arm description
    		 Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 50 mg, 100 mg, 150 mg, or 200 mg oral, administered as 1, 2, 3, or 4 50-mg tablets BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Arm title
    		 Cohort 2: Gefapixant>Placebo
    Arm description
    		 Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 7.5 mg, 15 mg, 30 mg, or 50 mg oral, administered as 1, 2, or 4 7.5-mg tablets or 1 50-mg tablet BID for 4 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Arm title
    		 Cohort 2: Placebo>Gefapixant
    Arm description
    		 Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Gefapixant, oral, administered BID for 16 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant: 7.5 mg, 15 mg, 30 mg, or 50 mg oral, administered as 1, 2, or 4 7.5-mg tablets or 1 50-mg tablet BID for 4 days

    Number of subjects in period 2
    		Cohort 1: Gefapixant>Placebo Cohort 1: Placebo>Gefapixant Cohort 2: Gefapixant>Placebo Cohort 2: Placebo>Gefapixant
    Started
    14
    13
    15
    15
    Completed
    14
    12
    14
    15
    Not completed
    0
    1
    1
    0
         Adverse event, non-fatal
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 1: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.

    Reporting group values
    		 Cohort 1: Gefapixant>Placebo Cohort 1: Placebo>Gefapixant Cohort 2: Gefapixant>Placebo Cohort 2: Placebo>Gefapixant Total
    Number of subjects
    		 15 14 15 15 59
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 6 9 8 8 31
        From 65-84 years
    		 9 5 7 7 28
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.5 ± 6.92 61.7 ± 7.77 60.7 ± 9.42 59.8 ± 12.8 -
    Sex: Female, Male
    Units: Participants
        Female
    		 13 12 12 12 49
        Male
    		 2 2 3 3 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 1 1 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 1 0 1
        White
    		 15 13 13 15 56
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1 1 3
        Not Hispanic or Latino
    		 14 14 14 14 56
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 1: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
    Reporting group title
    Cohort 1: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 1: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Gefapixant>Placebo
    Reporting group description
    		 Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.

    Reporting group title
    Cohort 2: Placebo>Gefapixant
    Reporting group description
    		 Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.

    Subject analysis set title
    Cohort 1 – Gefapixant>Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7-day washout period between treatment periods.

    Subject analysis set title
    Cohort 1 - Placebo>Gefalixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

    Subject analysis set title
    Cohort 2 – Gefapixant>Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2, there was a 14 to 21-day washout period between treatment periods.

    Subject analysis set title
    Cohort 2 - Placebo>Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo to gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2, there was a 14 to 21-day washout period between treatment periods.

    Subject analysis set title
    Cohort 1 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 100 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 150 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 200 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 7.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 7.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 15 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 30 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 30 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 30 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.

    Subject analysis set title
    Cohort 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.

    Subject analysis set title
    Cohort 2 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each.

    Subject analysis set title
    Cohort 1 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 100 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 150 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 200 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 100 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 150 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 200 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant 7.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 7.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 15 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Gefapixant 30 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 30 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 30 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 2 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50 mg tablet administered by mouth BID for 4 days.

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 50 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 100 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 150 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 150 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 200 mg tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Placebo for Gefapixant 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 1 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.

    Subject analysis set title
    Cohort 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 2 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 1 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.

    Subject analysis set title
    Cohort 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days

    Subject analysis set title
    Cohort 2 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 2 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 1 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 2 - Gefapixant
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 2 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each

    Subject analysis set title
    Cohort 2 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo tablet administered by mouth BID for 4 days each

    Primary: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1

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    End point title
    		 Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
    End point description
    Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    26
    25
    24
    25
    23
    22
    25
    25
    Units: Log coughs/hour
        geometric mean (confidence interval 95%)
    0.56 (0.43 to 0.72)
    0.95 (0.73 to 1.23)
    0.46 (0.34 to 0.61)
    0.95 (0.71 to 1.28)
    0.48 (0.35 to 0.65)
    0.90 (0.65 to 1.24)
    0.45 (0.33 to 0.63)
    1.06 (0.75 to 1.48)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0055
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -41.222
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.294
         upper limit
    		 -15.127
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -51.973
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.23
         upper limit
    		 -27.397
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0075
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -46.853
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -66.291
         upper limit
    		 -16.206
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -57.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -73.375
         upper limit
    		 -30.771

    Primary: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2

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    End point title
    		 Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
    End point description
    Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    29
    27
    Units: Log coughs/hour
        geometric mean (confidence interval 95%)
    0.80 (0.66 to 0.96)
    0.93 (0.77 to 1.13)
    0.67 (0.57 to 0.80)
    0.90 (0.75 to 1.08)
    0.53 (0.40 to 0.69)
    0.84 (0.64 to 1.10)
    0.44 (0.32 to 0.60)
    1.00 (0.72 to 1.38)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2542
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -14.691
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.307
         upper limit
    		 12.493
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0267
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -25.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.014
         upper limit
    		 -3.421
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0198
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -37.146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.345
         upper limit
    		 -7.3821
    Statistical analysis title
    		 gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimated percent change
    Point estimate
    -55.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.923
         upper limit
    		 -30.797

    Primary: Percent Change from Baseline in Awake Cough Frequency for Cohort 1

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    End point title
    		 Percent Change from Baseline in Awake Cough Frequency for Cohort 1 [1]
    End point description
    Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint.
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    26
    25
    24
    25
    23
    22
    25
    25
    Units: Percent Change
        arithmetic mean (standard deviation)
    -20.6 ± 84.29
    -0.1 ± 33.75
    -31.7 ± 70.27
    1.9 ± 35.18
    -22.0 ± 82.84
    -0.1 ± 39.55
    -27.9 ± 57.03
    15.1 ± 48.38
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Awake Cough Frequency for Cohort 2

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    End point title
    		 Percent Change from Baseline in Awake Cough Frequency for Cohort 2 [2]
    End point description
    Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint.
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    29
    27
    Units: Percent Change
        arithmetic mean (standard deviation)
    5.0 ± 125.05
    -3.8 ± 36.13
    -21.4 ± 39.32
    -6.4 ± 33.78
    -26.3 ± 61.01
    -1.1 ± 64.38
    -28.1 ± 74.90
    23.1 ± 92.60
    No statistical analyses for this end point

    Primary: Responder Analysis of Awake Cough Frequency for Cohort 1

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    End point title
    		 Responder Analysis of Awake Cough Frequency for Cohort 1 [3]
    End point description
    Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint.
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    26
    25
    24
    25
    23
    22
    25
    25
    Units: Percent Responders
    number (not applicable)
        % Reduction ≥70
    34.6
    0
    33.3
    0
    34.8
    4.5
    32.0
    0
        % Reduction ≥50
    46.2
    0
    50.0
    4.0
    47.8
    4.5
    44.0
    0
        % Reduction ≥30
    53.8
    12.0
    66.7
    16.0
    65.2
    22.7
    56.0
    16.0
    No statistical analyses for this end point

    Primary: Responder Analysis of Awake Cough Frequency for Cohort 2

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    End point title
    		 Responder Analysis of Awake Cough Frequency for Cohort 2 [4]
    End point description
    Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.
    End point type
    Primary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint.
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    29
    27
    Units: Percent Responders
    number (not applicable)
        % Reduction ≥70
    3.4
    3.6
    10.0
    0
    20.7
    3.4
    31.0
    3.7
        % Reduction ≥50
    13.8
    7.1
    20.0
    6.9
    31.0
    17.2
    41.4
    11.1
        % Reduction ≥30
    37.9
    14.3
    46.7
    20.7
    62.1
    31.0
    55.2
    22.2
    No statistical analyses for this end point

    Secondary: Change from Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1

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    End point title
    		 Change from Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1
    End point description
    Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    26
    25
    24
    25
    23
    22
    25
    25
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    -24.5 (-33.0 to -15.9)
    -5.5 (-14.2 to 3.3)
    -24.5 (-33.1 to -15.8)
    -0.1 (-8.8 to 8.7)
    -26.5 (-40.3 to -12.8)
    2.7 (-11.4 to 16.9)
    -27.5 (-37.9 to -17.0)
    2.2 (-8.5 to 12.8)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.2
         upper limit
    		 -6.8
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.7
         upper limit
    		 -12.1
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49
         upper limit
    		 -9.5
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.6
         upper limit
    		 -14.7

    Secondary: Change from Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2

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    End point title
    		 Change from Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2
    End point description
    Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    29
    27
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    -8.0 (-17.9 to 1.9)
    -1.1 (-11.1 to 9.0)
    -15.2 (-22.1 to -8.3)
    -1.7 (-8.8 to 5.3)
    -21.7 (-31.9 to -11.5)
    8.5 (-1.8 to 18.8)
    -21.9 (-32.8 to -11.0)
    4.7 (-6.5 to 16.0)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.332
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21
         upper limit
    		 7.2
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.3
         upper limit
    		 -3.6
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.7
         upper limit
    		 -15.7
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -26.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.3
         upper limit
    		 -11

    Secondary: Change from Baseline in Total (24 hours) Cough Frequency - Cohort 1

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    End point title
    		 Change from Baseline in Total (24 hours) Cough Frequency - Cohort 1
    End point description
    Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    26
    25
    24
    25
    23
    22
    25
    25
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    -16.6 (-22.4 to -10.9)
    -1.5 (-7.5 to 4.5)
    -17.6 (-24.1 to -11.0)
    -0.9 (-7.5 to 5.8)
    -18.0 (-26.1 to -9.9)
    1.5 (-6.8 to 9.8)
    -17.4 (-25.2 to -9.5)
    3.1 (-4.9 to 11.2)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.5
         upper limit
    		 -6.8
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.1
         upper limit
    		 -7.4
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.1
         upper limit
    		 -7.8
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.8
         upper limit
    		 -9.3

    Secondary: Change from Baseline in Total (24 hours) Cough Frequency - Cohort 2

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    End point title
    		 Change from Baseline in Total (24 hours) Cough Frequency - Cohort 2
    End point description
    Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    29
    27
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    -6.9 (-12.6 to -1.1)
    -2.7 (-8.6 to 3.1)
    -11.0 (-15.5 to -6.4)
    -3.8 (-8.4 to 0.9)
    -16.9 (-23.3 to -10.4)
    1.4 (-5.2 to 7.9)
    -15.9 (-21.0 to -9.9)
    1.8 (-4.4 to 7.9)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.315
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.3
         upper limit
    		 4
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.7
         upper limit
    		 -0.7
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.4
         upper limit
    		 -9.1
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -17.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.3
         upper limit
    		 -9

    Secondary: Change from Baseline in Sleep Cough Frequency - Cohort 1

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    End point title
    		 Change from Baseline in Sleep Cough Frequency - Cohort 1
    End point description
    Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    24
    24
    21
    24
    22
    22
    24
    25
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    -3.5 (-7.0 to 0.1)
    0.1 (-3.5 to 3.7)
    -3.1 (-6.8 to 0.6)
    -0.7 (-4.2 to 2.8)
    -2.0 (-4.8 to 0.7)
    -0.1 (-2.8 to 2.6)
    -3.6 (-7.0 to -0.1)
    0.2 (-3.2 to 3.6)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.169
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 1.6
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.341
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 2.6
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.311
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 1.9
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 1.1

    Secondary: Change from Baseline in Sleep Cough Frequency - Cohort 2

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    End point title
    		 Change from Baseline in Sleep Cough Frequency - Cohort 2
    End point description
    Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    29
    28
    30
    29
    29
    29
    28
    27
    Units: Coughs/hour
        least squares mean (confidence interval 95%)
    0.6 (-2.7 to 3.9)
    -0.6 (-3.9 to 2.8)
    -3.1 (-5.6 to -0.5)
    -2.5 (-5.1 to 0.2)
    -2.4 (-4.7 to -0.2)
    -1.6 (-3.8 to 0.7)
    -3.0 (-8.7 to 2.6)
    2.1 (-3.6 to 7.9)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.613
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 5.9
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.743
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 3.1
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.589
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 2.3
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.205
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.2
         upper limit
    		 2.9

    Secondary: Change from Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1

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    End point title
    		 Change from Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1
    End point description
    The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    27
    27
    26
    27
    26
    27
    28
    28
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.6 (-1.2 to -0.1)
    0.0 (-0.5 to 0.5)
    -1.1 (-1.8 to -0.5)
    0.1 (-0.5 to 0.8)
    -1.5 (-2.2 to -0.8)
    0.1 (-0.6 to 0.8)
    -1.6 (-2.4 to -0.8)
    0.1 (-0.7 to 0.9)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0811
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.1
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0097
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 -0.3
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0025
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -0.6
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 -0.5

    Secondary: Change from Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2

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    End point title
    		 Change from Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2
    End point description
    The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    30
    29
    30
    29
    30
    29
    29
    29
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -1.0 (-1.5 to -0.5)
    -0.3 (-0.8 to 0.2)
    -1.2 (-1.8 to -0.6)
    -0.3 (-0.9 to 0.3)
    -1.7 (-2.3 to -1.1)
    -0.3 (-1.0 to 0.3)
    -1.6 (-2.4 to -0.9)
    -0.5 (-1.3 to 0.2)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0506
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0447
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0026
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 -0.5
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0405
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 0

    Secondary: Change from Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): individual Domain and Total Scores for Cohort 1 and 2

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    End point title
    		 Change from Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): individual Domain and Total Scores for Cohort 1 and 2
    End point description
    The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. Participants' perception of their cough severity was assessed, based on the LCQ-Acute score, at Baseline and last day of dose. LCQ was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    27
    28
    30
    29
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    3.02 (1.61 to 4.42)
    -0.82 (-2.19 to 0.55)
    3.57 (2.27 to 4.87)
    0.05 (-1.28 to 1.37)
    Statistical analysis title
    		 Gefapixant Vs. Placebo Cohort 1
    Comparison groups
    Cohort 1 - Gefapixant v Cohort 1 - Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.88
         upper limit
    		 5.8
    Statistical analysis title
    		 Gefapixant vs. Placebo Cohort 2
    Comparison groups
    Cohort 2 - Gefapixant v Cohort 2 - Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.66
         upper limit
    		 5.38

    Secondary: Change from Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1

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    End point title
    		 Change from Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1
    End point description
    Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
    End point values
    		 Cohort 1 - Gefapixant 50 mg Cohort 1 - Placebo for Gefapixant 50 mg Cohort 1 - Gefapixant 100 mg Cohort 1 - Placebo for Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1 - Placebo for Gefapixant 150 mg Cohort 1 - Gefapixant 200 mg Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects analysed
    27
    28
    27
    27
    26
    27
    26
    27
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -14.4 (-23.4 to -5.5)
    -3.8 (-12.6 to 5.0)
    -26.3 (-36.0 to -16.6)
    -6.3 (-15.9 to 3.2)
    -28.8 (-39.1 to -18.4)
    -2.6 (-12.8 to 7.6)
    -31.5 (-41.9 to -21.0)
    2.3 (-8.0 to 12.6)
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 50 mg v Cohort 1 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.096
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.2
         upper limit
    		 1.9
    Statistical analysis title
    		 Gefapixant 100 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 100 mg v Cohort 1 - Placebo for Gefapixant 100 mg
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.6
         upper limit
    		 -6.3
    Statistical analysis title
    		 Gefapixant 150 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 150 mg v Cohort 1 - Placebo for Gefapixant 150 mg
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.7
         upper limit
    		 -11.6
    Statistical analysis title
    		 Gefapixant 200 mg vs. Placebo
    Comparison groups
    Cohort 1 - Gefapixant 200 mg v Cohort 1 - Placebo for Gefapixant 200 mg
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -33.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.4
         upper limit
    		 -19.1

    Secondary: Change from Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2

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    End point title
    		 Change from Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2
    End point description
    Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
    End point type
    Secondary
    End point timeframe
    Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
    End point values
    		 Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Placebo for Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Placebo for Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Placebo for Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects analysed
    30
    29
    30
    29
    30
    29
    29
    29
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -12.6 (-21.5 to -3.8)
    -6.2 (-15.2 to 2.9)
    -17.4 (-26.0 to -8.7)
    -10.0 (-18.7 to -1.2)
    -23.3 (-31.7 to -14.9)
    -7.7 (-16.2 to 0.9)
    -24.7 (-35.2 to -14.2)
    -9.3 (-19.9 to 1.4)
    Statistical analysis title
    		 Gefapixant 7.5 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 7.5 mg v Cohort 2 - Placebo for Gefapixant 7.5 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.311
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.1
         upper limit
    		 6.2
    Statistical analysis title
    		 Gefapixant 15 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 15 mg v Cohort 2 - Placebo for Gefapixant 15 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.232
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.7
         upper limit
    		 4.9
    Statistical analysis title
    		 Gefapixant 30 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 30 mg v Cohort 2 - Placebo for Gefapixant 30 mg
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.6
         upper limit
    		 -3.6
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Comparison groups
    Cohort 2 - Gefapixant 50 mg v Cohort 2 - Placebo for Gefapixant 50 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.4
         upper limit
    		 -0.5

    Other pre-specified: Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2
    End point description
    Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24 hour sound recordings were collected using a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    24 hours (while awake) on Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    26
    30
    29
    Units: Coughs/hour
        arithmetic mean (standard deviation)
    54.5 ± 41.09
    52.8 ± 40.44
    49.6 ± 44.01
    46.1 ± 39.82
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) Awake (0 - 8 hours) Cough Frequency for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) Awake (0 - 8 hours) Cough Frequency for Cohort 1 and Cohort 2
    End point description
    Awake (0 - 8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24 hour sound recordings were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    First 8 hours (while awake) on Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    26
    30
    29
    Units: Coughs/hour
        arithmetic mean (standard deviation)
    51.8 ± 41.09
    53.3 ± 42.30
    47.2 ± 42.09
    42.2 ± 39.42
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2
    End point description
    Total (0 - 24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours) for the monitoring period. 24 hour sound recordings were collected using a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    24 hours (while awake) on Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    26
    30
    29
    Units: Coughs/hour
        arithmetic mean (standard deviation)
    39.7 ± 28.38
    37.9 ± 27.46
    36.3 ± 32.28
    32.2 ± 27.97
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) for Sleep Cough Frequency for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) for Sleep Cough Frequency for Cohort 1 and Cohort 2
    End point description
    Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    First 8 hours (while asleep) on Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    27
    26
    30
    29
    Units: Coughs/hour
        arithmetic mean (standard deviation)
    8.3 ± 9.30
    7.8 ± 9.80
    10.1 ± 26.77
    5.6 ± 7.58
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) for the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) for the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 and Cohort 2
    End point description
    The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Days 0 and 22)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    28
    30
    28
    Units: Score on a scale
        arithmetic mean (standard deviation)
    4.2 ± 1.89
    3.7 ± 1.61
    4.5 ± 1.98
    4.5 ± 1.93
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) for the Acute Leicester Cough Questionnaire (LCQ) Instrument for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) for the Acute Leicester Cough Questionnaire (LCQ) Instrument for Cohort 1 and Cohort 2
    End point description
    The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. As per the Statistical Analysis Plan, each domain and total LCQ score change from baseline were analyzed without the treatment by dose interaction. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    28
    30
    29
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Psychological Domain Score
    3.8 ± 1.21
    4.1 ± 1.45
    3.9 ± 1.58
    4.1 ± 1.56
        Physical Domain Score
    4.4 ± 0.99
    4.7 ± 1.06
    4.8 ± 1.19
    5.0 ± 1.00
        Social Domain Score
    4.2 ± 1.22
    4.3 ± 1.21
    3.9 ± 1.57
    4.2 ± 1.57
        Total Acute Leicester Score
    12.3 ± 3.13
    13.1 ± 3.41
    12.6 ± 4.04
    13.3 ± 3.81
    No statistical analyses for this end point

    Other pre-specified: Baseline (Predose) for Cough Visual Analogue Scale (VAS) for Cohort 1 and Cohort 2

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    End point title
    		 Baseline (Predose) for Cough Visual Analogue Scale (VAS) for Cohort 1 and Cohort 2
    End point description
    Cough VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 (no cough) and 100 (most severe cough) mm. Baseline cough VAS is defined as average of screening and baseline cough VAS. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
    End point type
    Other pre-specified
    End point timeframe
    Screening, Days 0 and 22 (Baseline)
    End point values
    		 Cohort 1 - Gefapixant Cohort 1 - Placebo Cohort 2 - Gefapixant Cohort 2 - Placebo
    Number of subjects analysed
    28
    28
    30
    29
    Units: Score on a scale
        arithmetic mean (standard deviation)
    58.4 ± 18.66
    52.2 ± 19.21
    54.5 ± 24.26
    57.2 ± 23.71
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data collection is up to 11 weeks All-cause mortality is up to 22 weeks
    Adverse event reporting additional description
    Analysis population consisted of all randomized participants who received at least 1 dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cohort 1: Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 50 mg tablet administered by mouth twice daily (BID) for 4 days.

    Reporting group title
    Cohort 1: Gefapixant 100 mg
    Reporting group description
    		 Gefapixant 100 mg tablet administered by mouth BID or 4 days.

    Reporting group title
    Cohort 1 - Gefapixant 150 mg
    Reporting group description
    		 Gefapixant 150 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 1: Gefapixant 200 mg
    Reporting group description
    		 Gefapixant 200 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 1 - Placebo
    Reporting group description
    		 Placebo tablet administered by mouth BID for 4 days each.

    Reporting group title
    Cohort 2 - Gefapixant 7.5 mg
    Reporting group description
    		 Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 2 - Gefapixant 15 mg
    Reporting group description
    		 Gefapixant 15 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 2 - Gefapixant 30 mg
    Reporting group description
    		 Gefapixant 30 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 2 - Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 50 mg tablet administered by mouth BID for 4 days.

    Reporting group title
    Cohort 2- Placebo
    Reporting group description
    		 Placebo tablet administered by mouth BID for 4 days each.

    Serious adverse events
    		 Cohort 1: Gefapixant 50 mg Cohort 1: Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1: Gefapixant 200 mg Cohort 1 - Placebo Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2- Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Gefapixant 50 mg Cohort 1: Gefapixant 100 mg Cohort 1 - Gefapixant 150 mg Cohort 1: Gefapixant 200 mg Cohort 1 - Placebo Cohort 2 - Gefapixant 7.5 mg Cohort 2 - Gefapixant 15 mg Cohort 2 - Gefapixant 30 mg Cohort 2 - Gefapixant 50 mg Cohort 2- Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 28 (60.71%)
    8 / 28 (28.57%)
    4 / 26 (15.38%)
    6 / 26 (23.08%)
    4 / 28 (14.29%)
    6 / 30 (20.00%)
    1 / 30 (3.33%)
    13 / 30 (43.33%)
    9 / 30 (30.00%)
    2 / 29 (6.90%)
    Investigations
    Urine output decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    0
    2
    0
    Dysgeusia
         subjects affected / exposed
    13 / 28 (46.43%)
    6 / 28 (21.43%)
    4 / 26 (15.38%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    12 / 30 (40.00%)
    4 / 30 (13.33%)
    0 / 29 (0.00%)
         occurrences all number
    13
    6
    4
    1
    1
    2
    1
    12
    4
    0
    Hypogeusia
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 28 (7.14%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    2
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    0
    1
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 28 (3.57%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    0
    2
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal dryness
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    4 / 30 (13.33%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    4
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 28 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2015
    Amendment 1: Low-Dose Cohort 2 with an additional 30 subjects was added to the trial.
    03 Sep 2015
    Amendment 2: Changes in study objectives and endpoints and elimination of study sites in the United Kingdom.
    02 Oct 2015
    Amendment 3: Changes made to Renal/Urologic Symptom Inventory assessments, wash-out periods, and the follow-up of adverse events.

    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
    For support, Contact us.
    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
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