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    Clinical Trial Results:
    A Phase 3b Randomized, Double-blind, Placebo Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Gefapixant in Women with Chronic Cough and Stress Urinary Incontinence

    Summary
    EudraCT number
    		 2019-002321-29
    Trial protocol
    		 DE   GB   ES  
    Global end of trial date
    02 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Oct 2023
    First version publication date
    31 Aug 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    7264-042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04193176
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, 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
    22 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and safety of gefapixant, in improving symptoms of cough-induced stress urinary incontinence (SUI) in adult female participants with refractory or unexplained chronic cough. The primary hypothesis was that gefapixant is superior to placebo in reducing the frequency of cough-induced SUI episodes over 12 weeks.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    Colombia: 46
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Guatemala: 46
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Peru: 33
    Country: Number of subjects enrolled
    Russian Federation: 89
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Ukraine: 57
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    376
    EEA total number of subjects
    15
    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)
    276
    From 65 to 84 years
    100
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 376 randomized participants, 375 participants received treatment.

    Pre-assignment
    Screening details
    		 Participant flow as per the database cutoff date of 02Sep2022.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo administered as an oral tablet twice daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily as a placebo oral tablet matching gefapixant

    Arm title
    		 Gefapixant
    Arm description
    		 Participants received gefapixant at a dose of 45 mg administered as an oral tablet twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily as an oral tablet of 45 mg

    Number of subjects in period 1
    		Placebo Gefapixant
    Started
    190
    186
    Treated
    190
    185
    Completed
    184
    176
    Not completed
    6
    10
         Consent withdrawn by subject
    6
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo administered as an oral tablet twice daily for 12 weeks.

    Reporting group title
    Gefapixant
    Reporting group description
    		 Participants received gefapixant at a dose of 45 mg administered as an oral tablet twice daily for 12 weeks.

    Reporting group values
    		 Placebo Gefapixant Total
    Number of subjects
    		 190 186 376
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 133 143 276
        From 65-84 years
    		 57 43 100
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.6 ( 11.3 ) 56.2 ( 11.5 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 190 186 376
        Male
    		 0 0 0
    Region
    Region of participants
    Units: Subjects
        North America
    		 11 9 20
        Europe
    		 102 102 204
        Asia Pacific
    		 3 3 6
        Other
    		 74 72 146
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 18 16 34
        Asian
    		 3 6 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 3 3
        White
    		 143 137 280
        More than one race
    		 26 24 50
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 79 73 152
        Not Hispanic or Latino
    		 111 113 224
        Unknown or Not Reported
    		 0 0 0
    Primary cough diagnosis
    Primary type of cough diagnosis was categorized as either refractory chronic cough or unexplained chronic cough.
    Units: Subjects
        Refractory Chronic Cough
    		 149 141 290
        Unexplained Chronic Cough
    		 41 45 86
    Weight
    Mean weight of participants
    Units: kilograms
        arithmetic mean (standard deviation)
    		 75.6 ( 13.1 ) 75.9 ( 13.3 ) -
    Duration of Chronic Cough
    Duration of chronic cough in years for participants with data
    Units: Years
        arithmetic mean (standard deviation)
    		 5.1 ( 6.6 ) 5.3 ( 6.5 ) -
    Duration of Stress Urinary Incontinence (SUI)
    Duration of stress urinary incontinence in participants
    Units: Months
        arithmetic mean (standard deviation)
    		 53.8 ( 80.8 ) 43.4 ( 58.3 ) -
    Body mass index
    Mean body mass index of participants
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 29.7 ( 4.4 ) 29.7 ( 4.8 ) -
    Baseline Mean Weekly Cough Severity in Visual Analog Scale (VAS) in mm
    The Cough Severity VAS is a single-item question asking the participant to rate the severity of their cough “today” using a 100 mm VAS anchored with “No Cough” at 0 and “Extremely Severe Cough” at 100. Similar to the well-established use of VAS scores in chronic pain, the Cough Severity VAS measure provides a quick and easily-interpreted subjective assessment useful for clinicians to monitor improvement of their chronic cough patients following treatment. Baseline mean weekly cough severity in participants measured in Visual Analog Scale in mm is presented.
    Units: VAS (mm)
        arithmetic mean (standard deviation)
    		 69.5 ( 15.6 ) 69.3 ( 15.8 ) -
    Height
    Mean height of participants
    Units: centimeters
        arithmetic mean (standard deviation)
    		 159.6 ( 6.9 ) 159.8 ( 7.0 ) -
    Baseline Mean Daily Cough-Induced Stress Urinary Incontinence Episodes, 7-day Average
    Baseline Mean Daily Cough-Induced Stress Urinary Incontinence Episodes, 7-day Average for participants
    Units: Number of episodes
        arithmetic mean (standard deviation)
    		 4.7 ( 4.1 ) 4.7 ( 3.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo administered as an oral tablet twice daily for 12 weeks.

    Reporting group title
    Gefapixant
    Reporting group description
    		 Participants received gefapixant at a dose of 45 mg administered as an oral tablet twice daily for 12 weeks.

    Primary: Percent change from baseline in average daily cough-induced stress urinary incontinence (SUI) episodes at Week 12

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    End point title
    		 Percent change from baseline in average daily cough-induced stress urinary incontinence (SUI) episodes at Week 12
    End point description
    Cough-induced SUI episodes were assessed using an event-driven electronic Incontinence Diary where the participant recorded the main cause of each urinary incontinence episode as coughing, another stress reason, or other cause. Episodes of incontinence were recorded for the week before baseline and treatment visit. Average daily cough induced SUI episodes were calculated as (sum of daily cough-induced SUI episodes in a week)/number of days recorded. The analysis population consisted of all randomized participants who received at least 1 dose of study intervention and had incontinence frequency of at least 4 days in the 7-day period prior to the visit at Week 12. The percent change from baseline in the average daily cough-induced SUI episodes to Week 12 are presented.
    End point type
    Primary
    End point timeframe
    Baseline and week 12
    End point values
    		 Placebo Gefapixant
    Number of subjects analysed
    185
    183
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -41.09 (-46.74 to -35.45)
    -52.78 (-58.44 to -47.09)
    Statistical analysis title
    		 Superiority of Gefapixant versus Placebo
    Comparison groups
    Placebo v Gefapixant
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -11.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.67
         upper limit
    		 -3.67

    Secondary: Percentage of participants who discontinued study intervention due to AEs

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    End point title
    		 Percentage of participants who discontinued study intervention due to AEs
    End point description
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The analysis population consisted of all randomized participants who received at least one dose of study intervention. The percentage of participants who discontinued study intervention due to an adverse event are presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    End point values
    		 Placebo Gefapixant
    Number of subjects analysed
    190
    185
    Units: Percentage
        number (not applicable)
    1.1
    7.0
    No statistical analyses for this end point

    Secondary: Percentage of participants with adverse events

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    End point title
    		 Percentage of participants with adverse events
    End point description
    An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The analysis population consisted of all randomized participants who received at least one dose of study intervention. The percentage of participants who experienced an adverse event are presented.
    End point type
    Secondary
    End point timeframe
    Up to 16 Weeks
    End point values
    		 Placebo Gefapixant
    Number of subjects analysed
    190
    185
    Units: Percentage
        number (not applicable)
    37.4
    69.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All deaths and adverse events: up to 16 Weeks
    Adverse event reporting additional description
    Every participant is counted a single time for each applicable serious adverse event. A system organ class appears on this report only if one or more specific serious adverse events in that system organ class occurred.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Gefapixant
    Reporting group description
    		 Participants received gefapixant at a dose of 45 mg administered as an oral tablet twice daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo administered as an oral tablet twice daily for 12 weeks.

    Serious adverse events
    		 Gefapixant Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 185 (1.62%)
    2 / 190 (1.05%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal fissure
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 185 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 185 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Gefapixant Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 185 (56.22%)
    12 / 190 (6.32%)
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    35 / 185 (18.92%)
    1 / 190 (0.53%)
         occurrences all number
    36
    1
    Dysgeusia
         subjects affected / exposed
    57 / 185 (30.81%)
    4 / 190 (2.11%)
         occurrences all number
    59
    4
    Headache
         subjects affected / exposed
    13 / 185 (7.03%)
    5 / 190 (2.63%)
         occurrences all number
    14
    5
    Hypogeusia
         subjects affected / exposed
    14 / 185 (7.57%)
    0 / 190 (0.00%)
         occurrences all number
    14
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    10 / 185 (5.41%)
    2 / 190 (1.05%)
         occurrences all number
    10
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2020
    Amendment 2 included the addition of procedures/assessments required for specialized urine crystal analysis.
    17 Dec 2020
    Amendment 3 included removal of procedures/assessments for specialized urine crystal analysis added in Protocol Amendment 02 and other clarifications.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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