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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Month Study to Evaluate the Efficacy and Safety of MK-7264 in Adult Participants with Chronic Cough (PN027)

    Summary
    EudraCT number
    2017-000537-31
    Trial protocol
    CZ   ES   FR   DK   GB   PL   HU  
    Global end of trial date
    17 Aug 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jul 2021
    First version publication date
    28 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    7264-027
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03449134
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study will be to evaluate the efficacy of gefapixant in reducing cough frequency as measured over a 24-hour period at Week 12, and to evaluate the safety and tolerability of gefapixant. The primary hypothesis is that at least one gefapixant dose is superior to placebo in reducing coughs per hour (over 24 hours) at Week 12.
    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
    14 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 49
    Country: Number of subjects enrolled
    Canada: 44
    Country: Number of subjects enrolled
    Czechia: 53
    Country: Number of subjects enrolled
    Denmark: 42
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Japan: 34
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Peru: 46
    Country: Number of subjects enrolled
    Poland: 53
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Turkey: 22
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    United Kingdom: 65
    Country: Number of subjects enrolled
    United States: 123
    Worldwide total number of subjects
    732
    EEA total number of subjects
    227
    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)
    447
    From 65 to 84 years
    283
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of 732 participants randomized to the 52-week treatment period, 730 participants received at least 1 dose of study intervention. After the main study, 41 participants continued in an optional Off-Treatment (Off-Tx) Durability observational study period (no treatment).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received dose-matched placebo tablets twice daily (BID) during the 12-week main study period and 40-week extension period.
    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
    Participants receive dose-matched placebo tablets orally BID during the 12-week main study period and during the 40-week extension period.

    Arm title
    Gefapixant 15 mg BID
    Arm description
    Participants received a gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg BID during the 12-week main study period and 40-week extension period.
    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
    Participants receive placebo to gefapixant 45 mg tablet orally BID during the 12-week main study period and during the 40-week extension period.

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant 15 mg tablet administered orally BID during the 12-week main study period and during the 40-week extension period.

    Arm title
    Gefapixant 45 mg BID
    Arm description
    Participants received a gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the 12-week main study period and 40-week extension period.
    Arm type
    Experimental

    Investigational medicinal product name
    Gefapixant
    Investigational medicinal product code
    Other name
    MK-7264
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefapixant 45 mg tablet administered orally BID during the 12-week main study period and during the 40-week extension period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants receive placebo to gefapixant 15 mg tablet orally BID during the 12-week main study period and during the 40-week extension period.

    Number of subjects in period 1
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Started
    244
    244
    244
    Treated
    243
    244
    243
    Completed
    199
    200
    184
    Not completed
    45
    44
    60
         Physician decision
    2
    3
    3
         Site Closure
    1
    -
    -
         Adverse event, serious fatal
    2
    1
    -
         Screen Failure
    1
    -
    1
         Consent withdrawn by subject
    37
    39
    55
         Lost to follow-up
    2
    1
    1
    Period 2
    Period 2 title
    12-Week Off-Treatment Durability Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo: Off Tx
    Arm description
    Participants previously treated with dose-matched placebo BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Gefapixant 15 mg BID: Off Tx
    Arm description
    Participants previously treated with gefapixant 15 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Gefapixant 45 mg BID: Off Tx
    Arm description
    Participants previously treated with gefapixant 45 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    Placebo: Off Tx Gefapixant 15 mg BID: Off Tx Gefapixant 45 mg BID: Off Tx
    Started
    10
    18
    13
    Completed
    10
    18
    13
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants continued in the optional Off-Treatment Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received dose-matched placebo tablets twice daily (BID) during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 15 mg BID
    Reporting group description
    Participants received a gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg BID during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 45 mg BID
    Reporting group description
    Participants received a gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the 12-week main study period and 40-week extension period.

    Reporting group values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID Total
    Number of subjects
    244 244 244 732
    Age categorical
    Units: Participants
        Adults (18-64 years)
    147 152 148 447
        From 65-84 years
    97 91 95 283
        85 years and over
    0 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    57.9 ± 13.1 59.6 ± 11.7 59.5 ± 13.1 -
    Sex: Female, Male
    Units: Participants
        Female
    182 181 181 544
        Male
    62 63 63 188
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    7 6 8 21
        Asian
    35 35 34 104
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    4 3 4 11
        White
    190 195 187 572
        More than one race
    8 5 11 24
        Unknown or Not Reported
    0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    33 35 33 101
        Not Hispanic or Latino
    204 205 208 617
        Unknown or Not Reported
    7 4 3 14
    Geographic Region
    Geographic region of enrollment with 5 categories: Asia-Pacific, Europe, North America, Others, and Missing.
    Units: Subjects
        Asia Pacific
    35 34 34 103
        Europe
    121 123 122 366
        North America
    56 55 56 167
        Others
    31 32 32 95
        Missing
    1 0 0 1
    Baseline 24-hour Coughs per Hour
    24-hour objective coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) divided by 24 hours (denominator could be different if the recording period was actually <24 hours but ≥20 hours). Baseline assessment was based on 24-hour sound recordings using a digital recording device which recorded sounds from the lungs and trachea through a chest contact sensor, as well as ambient sounds through a lapel microphone. All participants with 24-hour Coughs per Hour data available at baseline were analyzed (n=232, 235, 237).
    Units: coughs/hour
        arithmetic mean (standard deviation)
    38.07 ± 79.42 26.79 ± 21.13 28.53 ± 37.14 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received dose-matched placebo tablets twice daily (BID) during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 15 mg BID
    Reporting group description
    Participants received a gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg BID during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 45 mg BID
    Reporting group description
    Participants received a gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the 12-week main study period and 40-week extension period.
    Reporting group title
    Placebo: Off Tx
    Reporting group description
    Participants previously treated with dose-matched placebo BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Reporting group title
    Gefapixant 15 mg BID: Off Tx
    Reporting group description
    Participants previously treated with gefapixant 15 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Reporting group title
    Gefapixant 45 mg BID: Off Tx
    Reporting group description
    Participants previously treated with gefapixant 45 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Primary: Model-Based Geometric Mean Ratio (GMR) of 24-hour Objective Coughs Per Hour (Week 12/Baseline)

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    End point title
    Model-Based Geometric Mean Ratio (GMR) of 24-hour Objective Coughs Per Hour (Week 12/Baseline)
    End point description
    24-hour objective coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) divided by 24 hours. Assessment was based on 24-hour sound recordings using a digital recording device which recorded sounds from the lungs and trachea through a chest contact sensor, as well as ambient sounds through a lapel microphone. A longitudinal analysis of covariance (ANCOVA) model was applied to log-transformed cough counts to determine geometric mean (GM) 24-hour objective coughs per hour at baseline and Week 12 on the original scale. The GMR corresponding to the Week 12 GM 24-hour objective coughs per hour divided by the Baseline GM 24-hour objective coughs per hour was reported for all treatment study arms. All randomized participants in the analysis model who had taken at least 1 dose of study intervention and provided at least 1 baseline and at least 1 Week 12 24-hour cough observation during the treatment period were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    222
    227
    217
    Units: ratio
        geometric mean (confidence interval 95%)
    0.47 (0.41 to 0.54)
    0.48 (0.41 to 0.55)
    0.38 (0.33 to 0.44)
    Statistical analysis title
    24-Hour Coughs/Hour ERR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Estimated relative reduction (ERR) relative to Placebo (PBO) (i.e. estimated percent change difference) was calculated by 100 (e**DIFF -1), where e = exponent of difference; and DIFF= treatment difference in change from baseline at Week 12 based on log transformed data.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.041 [1]
    Method
    ANCOVA
    Parameter type
    Estimated Percent Change Difference
    Point estimate
    -18.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.92
         upper limit
    -0.86
    Notes
    [1] - Comparison based on a longitudinal ANCOVA model that included treatment, visit, treatment-by-visit interaction, gender, region, log-transformed baseline value, and log-transformed baseline value-by-visit as covariates.
    Statistical analysis title
    24-Hour Coughs/Hour ERR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Estimated relative reduction (ERR) relative to Placebo (i.e. estimated percent change difference) was calculated by 100 (e**DIFF -1), where e = exponent of difference; and DIFF= treatment difference in change from baseline at Week 12 based on log transformed data.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.874 [2]
    Method
    ANCOVA
    Parameter type
    Estimated Percent Change Difference
    Point estimate
    1.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.13
         upper limit
    22.99
    Notes
    [2] - Comparison based on a longitudinal ANCOVA model that included treatment, visit, treatment-by-visit interaction, gender, region, log-transformed baseline value, and log-transformed baseline value-by-visit as covariates.

    Primary: Number of Participants Experiencing At Least One Adverse Event (AE) During Treatment and Follow-up

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    End point title
    Number of Participants Experiencing At Least One Adverse Event (AE) During Treatment and Follow-up [3]
    End point description
    An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with at least one AE during either the 52-week treatment period or 2-week telephone follow-up was reported for all treatment study arms. All randomized participants who received at least 1 dose of study intervention during the 52-week treatment period were analyzed. Per protocol, participants who continued in the optional Off-Treatment observational period were not included in the primary safety analysis.
    End point type
    Primary
    End point timeframe
    Up to approximately 54 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this endpoint.
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    243
    244
    243
    Units: Participants
    184
    186
    208
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Treatment Due to AEs

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    End point title
    Number of Participants Who Discontinued Treatment Due to AEs [4]
    End point description
    An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with at least one AE during either the 52-week treatment period or 2-week telephone follow-up was reported for all treatment study arms. All randomized participants who received at least 1 dose of study intervention during the 52-week treatment period were analyzed. Per protocol, participants who continued in the optional Off-Treatment observational period were not included in the primary safety analysis.
    End point type
    Primary
    End point timeframe
    Up to approximately 52 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this endpoint.
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    243
    244
    243
    Units: Participants
    14
    15
    51
    No statistical analyses for this end point

    Secondary: Model-Based Geometric Mean Ratio (GMR) of Awake Objective Coughs Per Hour (Week 12/Baseline)

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    End point title
    Model-Based Geometric Mean Ratio (GMR) of Awake Objective Coughs Per Hour (Week 12/Baseline)
    End point description
    Awake objective coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) while the participant is awake divided by the total duration (in hours) for the monitoring period that the participant was awake. Assessment was based on 24-hour sound recordings using a digital recording device. A longitudinal ANCOVA model was applied to log-transformed cough counts to determine GM awake objective coughs per hour at baseline and Week 12 on the original scale. The GMR corresponding to the Week 12 GM awake objective coughs per hour divided by the Baseline GM awake objective coughs per hour was reported for all treatment study arms. All randomized participants in the analysis model who had taken at least 1 dose of study intervention and provided at least 1 baseline and at least 1 Week 12 awake cough observation during the treatment period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    222
    227
    217
    Units: ratio
        geometric mean (confidence interval 95%)
    0.46 (0.40 to 0.53)
    0.47 (0.41 to 0.55)
    0.38 (0.33 to 0.44)
    Statistical analysis title
    Awake Coughs/Hour ERR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Estimated relative reduction (ERR) relative to Placebo (i.e. estimated percent change difference) was calculated by 100 (e**DIFF -1), where e = exponent of difference; and DIFF= treatment difference in change from baseline at Week 12 based on log transformed data.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.056 [5]
    Method
    ANCOVA
    Parameter type
    Estimated Percent Change Difference
    Point estimate
    -17.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.57
         upper limit
    0.5
    Notes
    [5] - Comparison based on a longitudinal ANCOVA model that included treatment, visit, treatment-by-visit interaction, gender, region, log-transformed baseline value, and log-transformed baseline value-by-visit as covariates.
    Statistical analysis title
    Awake Coughs/Hour ERR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Estimated relative reduction (ERR) relative to Placebo (i.e. estimated percent change difference) was calculated by 100 (e**DIFF -1), where e = exponent of difference; and DIFF= treatment difference in change from baseline at Week 12 based on log transformed data.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.77 [6]
    Method
    ANCOVA
    Parameter type
    Estimated Percent Change Difference
    Point estimate
    2.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.33
         upper limit
    25.19
    Notes
    [6] - Comparison based on a longitudinal ANCOVA model that included treatment, visit, treatment-by-visit interaction, gender, region, log-transformed baseline value, and log-transformed baseline value-by-visit as covariates.

    Secondary: Percentage of Participants (Model-Based) With a ≤ -30% Change from Baseline in 24-hour Objective Coughs Per Hour at Week 12

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    End point title
    Percentage of Participants (Model-Based) With a ≤ -30% Change from Baseline in 24-hour Objective Coughs Per Hour at Week 12
    End point description
    24-hour coughs/hour defined as the total number of cough events during the 24-hour monitoring period divided by 24 hours. Assessment based on 24-hour sound recordings using a digital recording device. Percent change in 24-hour coughs/hour = (change from baseline in 24-hour coughs per hour/baseline 24-hour coughs per hour) ×100%. Negative values indicate a decrease in cough rate, while positive values indicate an increase in cough rate. A participant considered a responder if percent change from baseline in 24-hour coughs/hour was ≤ -30% (or a ≥30% reduction from baseline); and considered a non-responder otherwise. Percentage of participants (logistic regression model-based) with a ≤ -30% change from baseline in 24-hour coughs/hour at Week 12 reported for all treatment study arms. All randomized participants in the analysis model who had taken ≥1 dose of study intervention and had available 24-hour cough data at baseline and ≥1 available post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    222
    227
    217
    Units: Percentage of Participants
        number (not applicable)
    65.9
    66.2
    69.9
    Statistical analysis title
    24-Hour Coughs/Hour OR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.416
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.86
    Statistical analysis title
    24-Hour Coughs/Hour OR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.948
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.55

    Secondary: Percentage of Participants (Model-Based) With a ≤ -1.3-point Change from Baseline in Mean Weekly Cough Severity Diary (CSD) Total Score at Week 12

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    End point title
    Percentage of Participants (Model-Based) With a ≤ -1.3-point Change from Baseline in Mean Weekly Cough Severity Diary (CSD) Total Score at Week 12
    End point description
    The CSD evaluates the frequency of cough, intensity of cough and disruption and has a total of 7 items, each with scores ranging from 0 (best) to 10 (worst). The total daily CSD score was the sum of these seven item scores (Min=0, Max=70). Mean weekly total score was defined as the average of mean total daily scores collected during the week prior to each visit. Baseline was defined as the average CSD scores collected during the week prior to Day 1 (Day -6 to Day 0). Participants were considered responders if the change from baseline in mean weekly CSD total score was ≤ -1.3 points (or a ≥1.3 point reduction from baseline); and considered non-responder otherwise. The percentage of participants with a ≤ -1.3 point change from baseline in CSD at Week 12 was reported for all treatment study arms. All randomized participants who received ≥1 dose of study intervention, had available CSD data at baseline and ≥1 available post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    237
    241
    234
    Units: Percentage of Participants
        number (not applicable)
    52.4
    62.1
    60.5
    Statistical analysis title
    CSD OR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline CSD score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.94
         upper limit
    2.05
    Statistical analysis title
    CSD OR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline CSD score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    2.18

    Secondary: Percentage of Participants (Model-Based) With a ≤ -2.7-point Change from Baseline in Mean Weekly CSD Total Score at Week 12

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    End point title
    Percentage of Participants (Model-Based) With a ≤ -2.7-point Change from Baseline in Mean Weekly CSD Total Score at Week 12
    End point description
    The CSD evaluates frequency of cough, intensity of cough and disruption and has a total of 7 items, each with scores ranging from 0 (best) to 10 (worst). The total daily CSD score was the sum of these seven item scores (Min=0, Max=70). Mean weekly total score was defined as the average of the mean total daily scores collected during the week prior to each visit. Baseline was defined as the average CSD scores collected during the week prior to Day 1 (Day -6 to Day 0). Participants were considered responders if the change from baseline in mean weekly CSD total score was ≤ -2.7 points (or a ≥2.7 point reduction from baseline); and considered non-responder otherwise. The percentage of participants with a ≤ -2.7 point change from baseline in CSD at Week 12 was reported for all treatment study arms. All randomized participants who had taken ≥1 dose of study intervention and had available CSD data at baseline and ≥1 available post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    237
    241
    234
    Units: Percentage of Participants
        number (not applicable)
    28.6
    37.9
    40.1
    Statistical analysis title
    CSD OR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline CSD score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.11
         upper limit
    2.54
    Statistical analysis title
    CSD OR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline CSD score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    2.3

    Secondary: Percentage of Participants (Model-Based) With a ≤ -30 millimeter (mm) Change from Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 12

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    End point title
    Percentage of Participants (Model-Based) With a ≤ -30 millimeter (mm) Change from Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 12
    End point description
    Cough severity was scored using the Cough Severity VAS, a single-item question asking the participant to rate the severity of their cough “today” using a 100 mm VAS (100-point scale) ranging from 0 (“No Cough”) to 100 (“Extremely Severe Cough”). Mean weekly VAS score was derived as the average of VAS scores collected during the week prior to each visit. Baseline was defined as the average VAS scores collected during the week prior to Day 1 (Day -6 to Day 0). A participant was considered a responder if the change from baseline in mean weekly Cough Severity VAS score was ≤-30 mm (or a ≥30 mm reduction from baseline); and considered non-responder otherwise. The percentage of participants with ≤ -30 mm change from baseline in Cough Severity VAS at Week 12 was reported for all treatment study arms. All randomized participants who had taken ≥1 dose of study intervention and had available Cough Severity VAS data at baseline and ≥1 available post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    237
    241
    234
    Units: Percentage of Participants
        number (not applicable)
    31.3
    36.7
    41.2
    Statistical analysis title
    Cough Severity VAS OR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline VAS score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    2.3
    Statistical analysis title
    Cough Severity VAS OR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, region, baseline VAS score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.89

    Secondary: Percentage of Participants (Model-Based) With a ≥1.3-point Change from Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 12

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    End point title
    Percentage of Participants (Model-Based) With a ≥1.3-point Change from Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 12
    End point description
    The LCQ assesses the impact of chronic cough on health-related quality of life. It consists of 19 items which are divided over 3 domains: Physical, Psychological, and Social. A 7-point Likert scale is used to rate each item. For each domain, the domain score (range 1-7) is the sum of individual item score within the domain divided by the number of items in the domain. LCQ total score is the sum of the three domain scores and ranges from 3-21; with a higher score corresponding to a better health status. A participant was considered a responder if the change from baseline in LCQ total score was ≥1.3-points (increase from baseline); and considered non-responder otherwise. The percentage of participants with a ≥1.3-point change from baseline in LCQ total score at Week 12 was reported for all treatment study arms. All randomized participants who had taken ≥1 dose of study intervention and had available LCQ data at baseline and ≥1 available post-baseline measurement were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Gefapixant 15 mg BID Gefapixant 45 mg BID
    Number of subjects analysed
    217
    226
    214
    Units: Percentage of Participants
        number (not applicable)
    61.3
    68.8
    67.3
    Statistical analysis title
    LCQ OR: PBO vs Gefapixant 45 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included visit, treatment-by-visit interaction, gender, region, baseline LCQ score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 45 mg BID
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.98
    Statistical analysis title
    LCQ OR: PBO vs Gefapixant 15 mg
    Statistical analysis description
    Comparison based on a logistic regression model that included visit, treatment-by-visit interaction, gender, region, baseline LCQ score, and the interaction of baseline (underlying continuous response) by visit as covariates.
    Comparison groups
    Placebo v Gefapixant 15 mg BID
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    2.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-Treatment Period (plus 2-week telephone follow-up): Up to Week 54; Off-Treatment (Off-Tx) Period: From Week 52 through Week 64 (approximately 12 weeks)
    Adverse event reporting additional description
    All-Cause Mortality (ACM) reported for all randomized participants. Serious and Nonserious AEs reported for participants treated during 52-Week Treatment Period. AEs reported separately for treatment period and optional Off-Tx Period. Per protocol, only ACM, drug-related serious and nonserious AEs, and pregnancies monitored during Off-Tx Period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0, 23.1
    Reporting groups
    Reporting group title
    Placebo: On Tx
    Reporting group description
    Participants received dose-matched placebo tablets twice daily (BID) during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 15 mg BID: On Tx
    Reporting group description
    Participants received a gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg BID during the 12-week main study period and 40-week extension period.

    Reporting group title
    Gefapixant 45 mg BID: On Tx
    Reporting group description
    Participants received a gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the 12-week main study period and 40-week extension period.

    Reporting group title
    Placebo: Off Tx
    Reporting group description
    Participants previously treated with dose-matched placebo BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Reporting group title
    Gefapixant 15 mg BID: Off Tx
    Reporting group description
    Participants previously treated with gefapixant 15 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Reporting group title
    Gefapixant 45 mg BID: Off Tx
    Reporting group description
    Participants previously treated with gefapixant 45 mg BID for 52 weeks during the main study and extension study periods were observed for up to 3 months during an optional Off-Treatment Durability study period (participants received no treatment).

    Serious adverse events
    Placebo: On Tx Gefapixant 15 mg BID: On Tx Gefapixant 45 mg BID: On Tx Placebo: Off Tx Gefapixant 15 mg BID: Off Tx Gefapixant 45 mg BID: Off Tx
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 243 (5.76%)
    17 / 244 (6.97%)
    13 / 243 (5.35%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    2
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cartilage injury
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin abrasion
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall cyst
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papilloma viral infection
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 244 (0.41%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 244 (0.00%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 244 (0.00%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo: On Tx Gefapixant 15 mg BID: On Tx Gefapixant 45 mg BID: On Tx Placebo: Off Tx Gefapixant 15 mg BID: Off Tx Gefapixant 45 mg BID: Off Tx
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 243 (53.09%)
    140 / 244 (57.38%)
    179 / 243 (73.66%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    1 / 13 (7.69%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    16 / 243 (6.58%)
    9 / 244 (3.69%)
    11 / 243 (4.53%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    21
    10
    18
    0
    0
    0
    Cough
         subjects affected / exposed
    10 / 243 (4.12%)
    14 / 244 (5.74%)
    16 / 243 (6.58%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    11
    14
    17
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    10 / 243 (4.12%)
    13 / 244 (5.33%)
    14 / 243 (5.76%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    14
    18
    14
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 243 (0.00%)
    3 / 244 (1.23%)
    33 / 243 (13.58%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    37
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    8 / 243 (3.29%)
    22 / 244 (9.02%)
    88 / 243 (36.21%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    9
    25
    101
    0
    0
    0
    Headache
         subjects affected / exposed
    31 / 243 (12.76%)
    34 / 244 (13.93%)
    29 / 243 (11.93%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    55
    57
    51
    0
    0
    0
    Hypogeusia
         subjects affected / exposed
    1 / 243 (0.41%)
    5 / 244 (2.05%)
    13 / 243 (5.35%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    5
    14
    0
    0
    0
    Taste disorder
         subjects affected / exposed
    2 / 243 (0.82%)
    2 / 244 (0.82%)
    24 / 243 (9.88%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    24
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 243 (5.76%)
    15 / 244 (6.15%)
    12 / 243 (4.94%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    19
    19
    23
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    6 / 243 (2.47%)
    7 / 244 (2.87%)
    13 / 243 (5.35%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    7
    7
    13
    0
    0
    0
    Nausea
         subjects affected / exposed
    13 / 243 (5.35%)
    8 / 244 (3.28%)
    17 / 243 (7.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    22
    8
    20
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 243 (3.29%)
    13 / 244 (5.33%)
    9 / 243 (3.70%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    8
    18
    12
    0
    0
    0
    Back pain
         subjects affected / exposed
    19 / 243 (7.82%)
    14 / 244 (5.74%)
    20 / 243 (8.23%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    21
    17
    27
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 243 (4.53%)
    20 / 244 (8.20%)
    11 / 243 (4.53%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    12
    25
    17
    0
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 243 (0.41%)
    1 / 244 (0.41%)
    1 / 243 (0.41%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    51 / 243 (20.99%)
    47 / 244 (19.26%)
    50 / 243 (20.58%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
    0 / 13 (0.00%)
         occurrences all number
    75
    60
    63
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 243 (0.41%)
    2 / 244 (0.82%)
    0 / 243 (0.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 243 (3.70%)
    18 / 244 (7.38%)
    13 / 243 (5.35%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    12
    20
    19
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    11 / 243 (4.53%)
    14 / 244 (5.74%)
    9 / 243 (3.70%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    14
    14
    13
    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
    15 Dec 2017
    Major changes of Amendment (AM) 1 include revision of eligibility criteria and editorial clarifications.
    27 Sep 2018
    Major changes of Amendment AM 2 include a clarification of treatment of co-morbid conditions, and an update of the estimated glomerular filtration rate (eGFR).

    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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