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    Clinical Trial Results:
    A Study to Assess the Effect of MK-7264 (AF-219) on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects

    Summary
    EudraCT number
    		 2015-002034-47
    Trial protocol
    		 GB  
    Global end of trial date
    20 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2017
    First version publication date
    01 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-7264-014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02476890
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IP Name: MK-7264, IP Name: AF-219
    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
    20 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of a single dose of 100 mg MK-7264 on cough reflex sensitivity to various challenge agents (capsaicin, citric acid, adenosine triphosphate [ATP], and distilled water) in both healthy and chronic cough participants. Cough challenge agents were administered in random order for each participant at Baseline (Day 0), and repeated in the same order at subsequent visits.
    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 participants involved in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    24
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The main purpose of the 6-day Screening period (Day -6 to Day -1) was to ensure that each participant met all the specified eligibility criteria. In addition, cough reflex sensitivity was measured at Screening by standard clinical methodology using cough challenge in response to 4 agents (capsaicin, citric acid, ATP, and distilled water).

    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, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo then MK-7264 100 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 1

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 2

    Arm title
    		 MK-7264 100 mg then placebo/Healthy (Sequence B)
    Arm description
    		 Healthy participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 1

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, administered as a single dose in treatment Period 2

    Arm title
    		 Placebo then MK-7264 100 mg/Chronic Cough (Sequence A)
    Arm description
    		 Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 1

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 2

    Arm title
    		 MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Arm description
    		 Chronic Cough participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 2

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 1

    Number of subjects in period 1
    		Placebo then MK-7264 100 mg/Healthy (Sequence A) MK-7264 100 mg then placebo/Healthy (Sequence B) Placebo then MK-7264 100 mg/Chronic Cough (Sequence A) MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Started
    6
    6
    12
    12
    Completed
    6
    6
    12
    12
    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, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo then MK-7264 100 mg/Healthy (Sequence A)
    Arm description
    		 Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 2

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, administered as a single dose in treatment Period 1

    Arm title
    		 MK-7264 100 mg then placebo/Healthy (Sequence B)
    Arm description
    		 Healthy participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 2

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 1

    Arm title
    		 Placebo then MK-7264 100 mg/Chronic Cough (Sequence A)
    Arm description
    		 Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 1

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 2

    Arm title
    		 MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Arm description
    		 Chronic Cough participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    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, administered as a single dose in treatment Period 2

    Investigational medicinal product name
    MK-7264 100 mg
    Investigational medicinal product code
    Other name
    AF-219
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK-7264 100 mg (2 x 50 mg), administered as a single dose in treatment Period 1

    Number of subjects in period 2
    		Placebo then MK-7264 100 mg/Healthy (Sequence A) MK-7264 100 mg then placebo/Healthy (Sequence B) Placebo then MK-7264 100 mg/Chronic Cough (Sequence A) MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Started
    6
    6
    12
    12
    Completed
    6
    6
    12
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 All participants who were randomised in the study

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 36 36
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 24 24
        From 65-84 years
    		 12 12
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ± 14.0 -
    Gender Categorical
    Units: Subjects
        Female
    		 32 32
        Male
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    Placebo then MK-7264 100 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    MK-7264 100 mg then placebo/Healthy (Sequence B)
    Reporting group description
    		 Healthy participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    Placebo then MK-7264 100 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Reporting group description
    		 Chronic Cough participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.
    Reporting group title
    Placebo then MK-7264 100 mg/Healthy (Sequence A)
    Reporting group description
    		 Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    MK-7264 100 mg then placebo/Healthy (Sequence B)
    Reporting group description
    		 Healthy participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    Placebo then MK-7264 100 mg/Chronic Cough (Sequence A)
    Reporting group description
    		 Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of MK-7264 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Reporting group title
    MK-7264 100 mg then placebo/Chronic Cough (Sequence B)
    Reporting group description
    		 Chronic Cough participants in Sequence B received a single dose of MK-7264 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

    Subject analysis set title
    MK-7264 100 mg/Healthy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy participants received MK-7264 100 mg in two treatment sequences and were administered cough challenge agents (capsaicin, citric acid, ATP, and distilled water) in random order at Baseline (Day 0), and repeated in the same order at subsequent visits 1 hour post-morning dose.

    Subject analysis set title
    Placebo/Healthy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy participants received placebo in two treatment sequences and were administered cough challenge agents (capsaicin, citric acid, ATP, and distilled water) in random order at Baseline (Day 0), and repeated in the same order at subsequent visits 1 hour post-morning dose.

    Subject analysis set title
    MK-7264 100 mg/Chronic Cough
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Chronic Cough participants received MK-7264 100 mg in two treatment sequences and were administered cough challenge agent (capsaicin, citric acid, ATP, and distilled water) in random order at Baseline (Day 0), and repeated in the same order at subsequent visits 1 hour post-morning dose.

    Subject analysis set title
    Placebo/Chronic Cough
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Chronic Cough participants received placebo in two treatment sequences and were administered cough challenge agents (capsaicin, citric acid, ATP, and distilled water) in random order at Baseline (Day 0), and repeated in the same order at subsequent visits 1 hour post-morning dose.

    Primary: Cough Reflex Sensitivity to Capsaicin in Participants Who Received MK-7264 100 mg and Placebo

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    End point title
    		 Cough Reflex Sensitivity to Capsaicin in Participants Who Received MK-7264 100 mg and Placebo
    End point description
    The concentration of capsaicin inducing at least 2 coughs (C2) and 5 coughs (C5), each averaged across 3 time points (at 1, 3, and 5 hours post-dose), on the treatment days were assessed in healthy and chronic cough participants who received a single dose of MK-7264 or placebo in Periods 1 & 2 combined. The concentrations of capsaicin for cough challenge ranged from 0.3-1000 µM. The challenge agent was prepared by dilution of a stock solution of capsaicin with saline. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or 5 (C5) coughs. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of cough reflex sensitivity in response to capsaicin challenge.
    End point type
    Primary
    End point timeframe
    5 hours
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: µM
    least squares mean (confidence interval 95%)
        C2 Response to Capsaicin (Periods 1 & 2)
    3.05 (2.6 to 3.5)
    3.04 (2.6 to 3.5)
    1.72 (1.3 to 2.1)
    1.41 (1.0 to 1.8)
        C5 Response to Capsaicin (Periods 1 & 2)
    4.46 (3.9 to 5.0)
    4.68 (4.1 to 5.3)
    2.31 (1.9 to 2.8)
    2.05 (1.6 to 2.5)
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a mixed effect repeated measures (MMRM) model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.9666
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.7
    Notes
    [1] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.5993
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 0.6
    Notes
    [2] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.2823
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.9
    Notes
    [3] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a mixed effect repeated measures (MMRM) model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.4287
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.9
    Notes
    [4] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Primary: Cough Reflex Sensitivity to Citric Acid in Participants Who Received MK-7264 100 mg and Placebo

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    End point title
    		 Cough Reflex Sensitivity to Citric Acid in Participants Who Received MK-7264 100 mg and Placebo
    End point description
    The concentration of citric acid inducing at least 2 coughs (C2) and 5 coughs (C5), each averaged across 3 time points (at 1, 3, and 5 hours post-dose), on the treatment days were assessed in healthy and chronic cough participants who received a single dose of MK-7264 or placebo in Periods 1 & 2 combined. The concentrations of citric acid for cough challenge ranged from 1 mM-3M. The challenge agent was prepared by dilution of a stock solution of citric acid with saline. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or 5 (C5) coughs. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of cough reflex sensitivity in response to citric acid challenge.
    End point type
    Primary
    End point timeframe
    5 hours
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: mM
    least squares mean (confidence interval 95%)
        C2 Response to Citric Acid (Periods 1 & 2)
    6.16 (5.6 to 6.8)
    5.61 (5.0 to 6.2)
    4.07 (3.6 to 4.6)
    3.84 (3.3 to 4.3)
        C5 Response to Citric Acid (Periods 1 & 2)
    7.12 (6.4 to 7.6)
    6.82 (6.1 to 7.6)
    4.74 (4.2 to 5.2)
    4.46 (4.0 to 5.0)
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.1771
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 1.4
    Notes
    [5] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.5473
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.3
    Notes
    [6] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.5169
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1
    Notes
    [7] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.4243
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 1
    Notes
    [8] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Primary: Cough Reflex Sensitivity to ATP in Participants Who Received MK-7264 100 mg and Placebo

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    End point title
    		 Cough Reflex Sensitivity to ATP in Participants Who Received MK-7264 100 mg and Placebo
    End point description
    The concentration of ATP inducing at least 2 coughs (C2) and 5 coughs (C5), each averaged across 3 time points (at 1, 3, and 5 hours post-dose), on the treatment days were assessed in healthy and chronic cough participants who received a single dose of MK-7264 or placebo in Periods 1 & 2 combined. The concentrations of ATP for cough challenge ranged from 0.1 mM-300 mM. The challenge agent was prepared by dilution of a stock solution of ATP with saline. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or 5 (C5) coughs. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of cough reflex sensitivity in response to ATP challenge.
    End point type
    Primary
    End point timeframe
    5 hours
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: mM
    least squares mean (confidence interval 95%)
        C2 Response to ATP (Periods 1 & 2)
    4.79 (4.0 to 5.6)
    3.90 (3.1 to 4.7)
    2.90 (2.3 to 3.5)
    1.36 (0.8 to 2.0)
        C5 Response to ATP (Periods 1 & 2)
    5.61 (5.3 to 5.9)
    4.73 (4.3 to 5.1)
    3.52 (2.9 to 4.2)
    2.22 (1.6 to 2.9)
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.1125
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 2
    Notes
    [9] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.0029
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.4
    Notes
    [10] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM Analysis: C2 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0006
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.4
    Notes
    [11] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.
    Statistical analysis title
    		 MMRM Analysis: C5 Response (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.0067
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 2.2
    Notes
    [12] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Primary: Cough Reflex Sensitivity to Distilled Water in Participants Who Received MK-7264 100 mg and Placebo

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    End point title
    		 Cough Reflex Sensitivity to Distilled Water in Participants Who Received MK-7264 100 mg and Placebo
    End point description
    The concentration of distilled water inducing at least 2 coughs (C2) and 5 coughs (C5), each averaged across 3 time points (at 1, 3, and 5 hours post-dose), on the treatment days were assessed in healthy and chronic cough participants who received a single dose of MK-7264 or placebo in Periods 1 & 2 combined. The concentrations of distilled water for cough challenge ranged from 20%-100%. The challenge agent was prepared by dilution of distilled water with saline. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or 5 (C5) coughs. The analysed population was all treated participants who had at least 1 post-dose primary endpoint assessment of cough reflex sensitivity in response to distilled water challenge.
    End point type
    Primary
    End point timeframe
    5 hours
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: % concentration
    least squares mean (confidence interval 95%)
        C2 Response to Distilled Water(Periods 1 & 2)
    4.72 (4.6 to 4.8)
    4.34 (4.2 to 4.4)
    4.42 (4.3 to 4.5)
    4.12 (4.0 to 4.2)
        C5 Response to Distilled Water(Periods 1 & 2)
    4.85 (4.6 to 5.1)
    4.61 (4.4 to 4.8)
    4.51 (4.4 to 4.6)
    4.24 (4.1 to 4.4)
    Statistical analysis title
    		 MMRM: C2 Reponse (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.5
    Notes
    [13] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM: C5 Response (Healthy)
    Statistical analysis description
    Treatment comparison was performed using a MMRM model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Healthy v Placebo/Healthy
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.1798
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.6
    Notes
    [14] - This was a crossover study, and the same number of healthy participants (n=12) received two comparative treatments. As such, 12 participants were analysed, not 24 participants.
    Statistical analysis title
    		 MMRM: C2 Reponse (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a mixed effect repeated measures (MMRM) model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0011
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.5
    Notes
    [15] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.
    Statistical analysis title
    		 MMRM: C5 Reponse (Chronic Cough)
    Statistical analysis description
    Treatment comparison was performed using a mixed effect repeated measures (MMRM) model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0023
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.4
    Notes
    [16] - This was a crossover study, and the same number of chronic cough participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Secondary: Change From Baseline in Cough Severity VAS After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)

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    End point title
    		 Change From Baseline in Cough Severity VAS After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)
    End point description
    Chronic cough participants completed a visual analogue scale (VAS) prior to dosing on the treatment day in each treatment period, and one hour after the final cough challenge on the treatment days. Participants used a 100mm VAS scale of cough severity from ‘No Cough’ (0) up to ‘Worst Cough’ (100). They were instructed to draw a line on the scale to indicate how severe they felt their cough was during the previous 1 hour on the treatment days. The analysed population was all treated chronic cough participants who had at least 1 post-dose primary endpoint assessment of cough severity VAS.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    24
    24
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -26.2 (-36.2 to -16.2)
    -8.2 (-18.7 to 2.2)
    Statistical analysis title
    		 Cough Severity VAS Analysis
    Statistical analysis description
    Treatment comparison was performed using a mixed effect repeated measures (MMRM) model that includes fixed effects for period, treatment group, and all interaction terms of treatment, timepoint, and period, and the baseline value (on the log scale) as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.0037
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.8
         upper limit
    		 -6.2
    Notes
    [17] - This was a crossover study, and the same number of participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Secondary: Change From Baseline in Urge to Cough VAS After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)

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    End point title
    		 Change From Baseline in Urge to Cough VAS After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)
    End point description
    Chronic cough participants completed a VAS prior to dosing on the treatment day in each treatment period, and one hour after the final cough challenge on the treatment days. Participants used a 100mm scale to record the severity of their urge to cough but marked at the extremes as ‘No urge-to-cough’ (0) and ‘Worst urge-to-cough’ (100). They were instructed to draw a single vertical line on the scale to indicate how severe their urge to cough was during the previous 1 hour on the treatment days. The analysed population was all treated chronic cough participants who had at least 1 post-dose primary endpoint assessment of urge to cough VAS.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    24
    24
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -29.8 (-38.9 to -20.7)
    -11.7 (-20.9 to -2.6)
    Statistical analysis title
    		 Urge to Cough VAS Analysis
    Statistical analysis description
    The mixed effect model included fixed effects for treatment group, period, the treatment-by-period interaction, and the Baseline value as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.1
         upper limit
    		 -7
    Notes
    [18] - This was a crossover study, and the same number of participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Secondary: Change From Baseline in Cough Frequency After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)

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    End point title
    		 Change From Baseline in Cough Frequency After Cough Challenge Testing in Participants Who Received MK-7264 100 mg and Placebo (Chronic Cough Participants Only)
    End point description
    An ambulatory cough recording device was attached to chronic cough participants. The device recorded all sounds the participant made during cough monitoring (from post-cough challenge to approximately 24 hours later). The resulting recording was processed by validated custom written software which determined the total number of coughs and coughs per hour. The change from Baseline in objective cough frequency was measured on the treatment days. The analysed population was all treated chronic cough participants who had at least 1 post-dose primary endpoint assessment of cough frequency.
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    24
    24
    Units: Counts/hr
        least squares mean (confidence interval 95%)
    -7.7 (-10.1 to -5.3)
    -4.1 (-6.5 to -1.7)
    Statistical analysis title
    		 Cough Frequency Analysis
    Statistical analysis description
    The mixed effect model included fixed effects for treatment group, period, the treatment-by-period interaction, and the Baseline value as a covariate.
    Comparison groups
    MK-7264 100 mg/Chronic Cough v Placebo/Chronic Cough
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.0075
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 -1
    Notes
    [19] - This was a crossover study, and the same number of participants (n=24) received two comparative treatments. As such, 24 participants were analysed, not 48 participants.

    Secondary: Percentage of Participants Who Experienced One or More Adverse Events During Study Treatment and Follow up

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events During Study Treatment and Follow up
    End point description
    A secondary endpoint of the trial was the percentage of participants receiving MK-7264 100 mg or placebo who had at least 1 adverse event (AE) during the treatment periods (including washout periods) in addition to 14 days (+3 days) until a post-treatment follow-up visit. The relative number (n/N [%]) of participants in any treatment group with at least 1 AE was assessed for days 1-18. The analysed population was all randomised participants who took at least 1 dose of study treatment and had assessment of AE occurrence.
    End point type
    Secondary
    End point timeframe
    18 days
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: Percentage of participants
        number (not applicable)
    100.0
    50.0
    95.8
    33.3
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
    End point description
    A secondary endpoint of the trial was the percentage of participants receiving MK-7264 100 mg or placebo who discontinued treatment due to an AE. The relative number (n/N [%]) of participants who discontinued treatment due to an AE. The analysed population was all randomised participants who took at least 1 dose of study treatment and had assessment of discontinuation due to an AE.
    End point type
    Secondary
    End point timeframe
    4 days
    End point values
    		 MK-7264 100 mg/Healthy Placebo/Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Number of subjects analysed
    12
    12
    24
    24
    Units: Percentge of participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    MK-7264 100 mg/Healthy
    Reporting group description
    		 -

    Reporting group title
    Placebo /Healthy
    Reporting group description
    		 -

    Reporting group title
    MK-7264 100 mg/Chronic Cough
    Reporting group description
    		 -

    Reporting group title
    Placebo/Chronic Cough
    Reporting group description
    		 -

    Serious adverse events
    		 MK-7264 100 mg/Healthy Placebo /Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-7264 100 mg/Healthy Placebo /Healthy MK-7264 100 mg/Chronic Cough Placebo/Chronic Cough
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    6 / 12 (50.00%)
    21 / 24 (87.50%)
    7 / 24 (29.17%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    6 / 12 (50.00%)
    1 / 12 (8.33%)
    7 / 24 (29.17%)
    0 / 24 (0.00%)
         occurrences all number
    6
    1
    7
    0
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    2
    1
    Dysgeusia
         subjects affected / exposed
    9 / 12 (75.00%)
    1 / 12 (8.33%)
    16 / 24 (66.67%)
    0 / 24 (0.00%)
         occurrences all number
    9
    1
    16
    0
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 12 (25.00%)
    6 / 24 (25.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    6
    2
    Hypogeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 12 (0.00%)
    6 / 24 (25.00%)
    1 / 24 (4.17%)
         occurrences all number
    4
    0
    6
    1
    Dyspepsia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Hypoaesthesia oral
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 12 (0.00%)
    4 / 24 (16.67%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    6
    0
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    2
    1
    Oral disorder
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 12 (8.33%)
    4 / 24 (16.67%)
    2 / 24 (8.33%)
         occurrences all number
    1
    1
    6
    2
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dry throat
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Increased upper airway secretion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngeal disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngeal hypoaesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    2 / 24 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    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
    17 Sep 2015
    Study treatment (AF-219) was changed from "100 mg BID, administered as two 50 mg tablets BID" to "100 mg, administered as two 50 mg tablets".
    19 Apr 2016
    A screening procedure was amended (i. e., spirometry in healthy participants only), and exclusion criteria for cough were clarified.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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