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    Clinical Trial Results:
    A Randomised, Double-Blind, Double-Dummy, Placebo-Controlled, Three-Way Cross-over Study to Evaluate the Effect of AF-219 on Methacholine Hyper-reactivity in Subjects with Asthma

    Summary
    EudraCT number
    		 2013-003566-13
    Trial protocol
    		 GB  
    Global end of trial date
    15 Mar 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Apr 2021
    First version publication date
    30 Dec 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update for consistency with ClinicalTrials.gov Results posting

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AF219-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01993329
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-7264-009
    Sponsors
    Sponsor organisation name
    Merck, Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck, Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the PC20 response (concentration of methacholine required to cause at least a 20% fall in lung function) of two dose levels of AF-219 compared with placebo in participants with asthma after provocation with methacholine.
    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. The following additional measure defined for this individual study was in place for the protection of trial subjects: allowed prior and concomitant medications were short acting inhaled β2-agonists (SABA) administered as rescue medication. A minimum period of 8 hours was to elapse between the use of rescue (SABA) and spirometry measurements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 20 participants were enrolled, randomized and treated.

    Pre-assignment
    Screening details
    		 A Screening Phase of up to 21 days ensured that each participant met all the specified inclusion and exclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Arm description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 50 mg BID for 4 days

    Arm title
    		 Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Arm description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 50 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 300 mg 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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 300 mg 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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg 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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg 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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Number of subjects in period 1
    		Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Started
    3
    4
    3
    3
    3
    4
    Completed
    3
    4
    3
    3
    3
    4
    Period 2
    Period 2 title
    Wash-out
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Arm description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Arm description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Started
    3
    4
    3
    3
    3
    4
    Completed
    3
    4
    3
    3
    3
    4
    Period 3
    Period 3 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Arm description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 300 mg BID for 4 days

    Arm title
    		 Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Arm description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg 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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 50 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg 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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 50 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 300 mg BID for 4 days

    Number of subjects in period 3
    		Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Started
    3
    4
    3
    3
    3
    4
    Completed
    3
    4
    3
    3
    3
    3
    Not completed
    0
    0
    0
    0
    0
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    1
    Period 4
    Period 4 title
    Wash-out
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Arm description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Arm description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Started
    3
    4
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3
    3
    Not completed
    0
    1
    0
    0
    0
    0
         Personal reasons
    -
    1
    -
    -
    -
    -
    Period 5
    Period 5 title
    Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Arm description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg 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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Arm title
    		 Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Arm description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 300 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg 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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Arm title
    		 Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Arm description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant at 50 mg 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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant 300 mg 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
    Matching placebo to mimic gefapixant 50 mg BID for 4 days

    Arm title
    		 Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Arm description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    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
    Matching placebo to mimic gefapixant 300 mg BID for 4 days

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    AF-219 MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant 50 mg BID for 4 days

    Number of subjects in period 5
    		Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Started
    3
    3
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group values
    		 Gefapixant 50 mg>Gefapixant 300 mg>Placebo Gefapixant 50 mg>Placebo>Gefapixant 300 mg Gefapixant 300 mg>Gefapixant 50 mg>Placebo Gefapixant 300 mg>Placebo>Gefapixant 50 mg Placebo> Gefapixant 50 mg>Gefapixant 300 mg Placebo> Gefapixant 300 mg>Gefapixant 50 mg Total
    Number of subjects
    		 3 4 3 3 3 4 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 3 4 3 3 3 4 20
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.7 ± 7.0 27.5 ± 7.6 43.3 ± 7.6 31.3 ± 8.0 52.7 ± 8.1 40.0 ± 14.3 -
    Sex: Female, Male
    Units:
        Female
    		 1 1 2 0 1 2 7
        Male
    		 2 3 1 3 2 2 13
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0
        White
    		 3 4 3 3 3 4 20
        More than one race
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 0 0
        Not Hispanic or Latino
    		 3 4 3 3 3 4 20
        Unknown or Not Reported
    		 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3
    Reporting group title
    Gefapixant 50 mg>Gefapixant 300 mg>Placebo
    Reporting group description
    		 Gefapixant 50 mg twice daily (BID) on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2 followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 50 mg>Placebo>Gefapixant 300 mg
    Reporting group description
    		 Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Gefapixant 50 mg>Placebo
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Gefapixant 300 mg>Placebo>Gefapixant 50 mg
    Reporting group description
    		 Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 50 mg>Gefapixant 300 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Reporting group title
    Placebo> Gefapixant 300 mg>Gefapixant 50 mg
    Reporting group description
    		 Placebo BID on Days 1-3 and once daily in the morning Day 4 in Period 1, followed by a washout period of ≥7 days, then Gefapixant 300 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 2, followed by a washout period of ≥7 days, then Gefapixant 50 mg BID on Days 1-3 and once daily in the morning Day 4 in Period 3

    Subject analysis set title
    Gefapixant 50
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received gefapixant 50 mg twice daily for 3.5 days during one period of the study

    Subject analysis set title
    Gefapixant 300
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received gefapixant 300 mg twice daily for 3.5 days during one period of the study

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received placebo twice daily for 3.5 days during each period of the study

    Subject analysis set title
    Screening
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Screening (Day -21 to Day -1)

    Primary: Provocative Concentration (PC20) After Methacholine Challenge

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    End point title
    		 Provocative Concentration (PC20) After Methacholine Challenge
    End point description
    The provocative concentration (PC) of inhaled methacholine required to reduce forced expiratory volume in 1 second (FEV1) by 20% (PC20) was calculated from the methacholine challenge at screening and 2 hours (+15 minutes) post dose on Day 3 of each Treatment Period using a five-breath dosimeter method. The primary endpoint was the methacholine PC20 value normalized by means of a log (base 2) transformation, at 2 dose levels compared with placebo in participants with asthma following provocation with methacholine. Analysis population included all randomized participants who received at least 1 dose of study medication and had any postdose efficacy evaluations for a given Treatment Period and who completed all 3 Treatment Periods.
    End point type
    Primary
    End point timeframe
    Screening (Day -21 to Day -1) and Day 3
    End point values
    		 Gefapixant 50 Gefapixant 300 Placebo
    Number of subjects analysed
    18
    18
    18
    Units: log [mg/mL]
        geometric mean (geometric coefficient of variation)
    0.91 ± 214.4
    0.84 ± 181.0
    0.82 ± 260.1
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Statistical analysis description
    Analysis was based on an ANOVA model with log (base 2) PC20 methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 50 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.616
    Method
    		 ANOVA
    Parameter type
    		 Geometric means ratio
    Point estimate
    1.108
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.734
         upper limit
    		 1.673
    Statistical analysis title
    		 Gefapixant 50 mg vs. Gefapixant 300 mg
    Statistical analysis description
    Analysis was based on an ANOVA model with log (base 2) PC20 methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 50 v Gefapixant 300
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.671
    Method
    		 ANOVA
    Parameter type
    		 Geometric means ratio
    Point estimate
    0.917
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.607
         upper limit
    		 1.384
    Statistical analysis title
    		 Gefapixant 300 mg vs. Placebo
    Statistical analysis description
    Analysis was based on an ANOVA model with log (base 2) PC20 methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 300 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.939
    Method
    		 ANOVA
    Parameter type
    		 Geometric means ratio
    Point estimate
    1.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.673
         upper limit
    		 1.534

    Secondary: Highest FEV1 After Methacholine Challenge

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    End point title
    		 Highest FEV1 After Methacholine Challenge
    End point description
    Serial FEV1 was measured post inhalation of methacholine challenges for 90 minutes. The highest FEV1 at 5, 15, 30, 45, 60, and 90 minutes following methacholine challenge were evaluated for each subject. The minimum highest FEV1 was derived using the first three available measures that cover the first 30 minutes after the challenge. Analysis population included all randomized participants who received at least 1 dose of study medication and had any postdose efficacy evaluations for a given Treatment Period and who completed all 3 Treatment Periods.
    End point type
    Secondary
    End point timeframe
    Screening (Day -21 to Day -1) and Day 3
    End point values
    		 Gefapixant 50 Gefapixant 300 Placebo Screening
    Number of subjects analysed
    18
    18
    18
    18
    Units: Liters
    arithmetic mean (standard deviation)
        + 5 minutes
    2.53 ± 0.70
    2.43 ± 0.71
    2.54 ± 0.75
    2.44 ± 0.66
        +15 minutes
    2.72 ± 0.80
    2.67 ± 0.83
    2.77 ± 0.84
    2.69 ± 0.75
        +30 minutes
    2.93 ± 0.88
    2.83 ± 0.86
    2.94 ± 0.89
    2.86 ± 0.82
        +45 minutes
    3.02 ± 0.88
    2.99 ± 0.90
    3.03 ± 0.93
    2.93 ± 0.83
        +60 minutes
    3.11 ± 0.93
    3.06 ± 0.91
    3.14 ± 0.96
    2.99 ± 0.84
        +90 minutes
    3.15 ± 0.93
    3.12 ± 0.90
    3.18 ± 0.95
    3.10 ± 0.88
        Minimum Highest FEV1
    2.53 ± 0.70
    2.43 ± 0.71
    2.54 ± 0.75
    2.44 ± 0.66
    Statistical analysis title
    		 Gefapixant 300 mg vs Placebo
    Statistical analysis description
    Analysis is based on an ANOVA model with minimum highest FEV1 after methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 300 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.066
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.008
    Statistical analysis title
    		 Gefapixant 50 mg vs. Gefapixant 300 mg
    Statistical analysis description
    Analysis is based on an ANOVA model with minimum highest FEV1 after methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 50 v Gefapixant 300
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.099
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.218
         upper limit
    		 0.02
    Statistical analysis title
    		 Gefapixant 50 mg vs. Placebo
    Statistical analysis description
    Analysis is based on an ANOVA model with minimum highest FEV1 after methacholine challenge at each period as dependent variable, treatment and period as fixed effects and participant as random effect.
    Comparison groups
    Gefapixant 50 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.843
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.131
         upper limit
    		 0.107

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 42 days
    Adverse event reporting additional description
    All-cause mortality events were assessed for all randomized participants. Non-serious and Serious AEs were assessed for all participants who were randomized and received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Gefapixant 50 mg
    Reporting group description
    		 Participants received gefapixant 50 mg twice daily for 3.5 days during one period of the study

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo twice daily for 3.5 days during each period of the study

    Reporting group title
    Gefapixant 300 mg
    Reporting group description
    		 Participants received gefapixant 300 mg twice daily for 3.5 days during one period of the study

    Serious adverse events
    		 Gefapixant 50 mg Placebo Gefapixant 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Gefapixant 50 mg Placebo Gefapixant 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 19 (84.21%)
    8 / 20 (40.00%)
    19 / 19 (100.00%)
    Injury, poisoning and procedural complications
    Soft tissue injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 19 (42.11%)
    6 / 20 (30.00%)
    6 / 19 (31.58%)
         occurrences all number
    9
    6
    6
    Dysgeusia
         subjects affected / exposed
    13 / 19 (68.42%)
    0 / 20 (0.00%)
    18 / 19 (94.74%)
         occurrences all number
    13
    0
    18
    Hypogeusia
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    General disorders and administration site conditions
    Thirst
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Macule
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2013
    Amendment 1: The main significant changes were to the Borg CR 10 Scale® for use in providing a measure of participants’ perception of dyspnea, changes in procedures for breaking the blind and screening measures.
    14 Mar 2014
    Amendment 2: The main significant changes were that the population used for analysis was changed from the intent-to-treat population to the per protocol population as well as changes to the procedures for protocol deviations and the analysis plans.

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

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