Gefapixant

Participants will be asked to complete the LCQ to assess the impact of their cough severity on health related quality of life (HRQoL) over the past 2 weeks. The LCQ is a 19-item, cough-specific HRQoL questionnaire. Each item on the LCQ assesses symptoms using a 7-point scale ranging from 1 to 7. The LCQ contains three domains on physical, psychological, and social functioning, and each domain score is calculated as the mean score of the items (range: 1 to 7) within the domain. The LCQ total score is the sum of the 3 domains, with a range from 3 (lowest total score) to 21 (highest total score). Higher scores indicate better HRQoL. The change from baseline in LCQ total score is calculated.

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 percent change from baseline in the average daily cough-induced SUI episodes to Week 12 are presented.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

24-hour coughs per hour was defined as the average hourly cough frequency based on 24-hour sound recordings using a digital recording device (cough monitor). A longitudinal analysis of covariance (ANCOVA) model was applied to log-transformed cough data to determine geometric mean (GM) 24-hour coughs per hour at baseline and week 24. The GMR (Week 24 GM 24-hour coughs per hour divided by Baseline GM 24-hour coughs per hour) is reported.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

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). 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.

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.

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 who discontinued study intervention during the 52-week treatment period due to an AE for which the action taken was listed as 'drug withdrawn' was reported for all treatment study arms.

Pelvic pain (cyclic pain associated with menses, and non-cyclic pain not associated with menses) severity score was measured using a 0-10 numeric rating scale (NRS), with 0 representing no pain and 10 representing extremely severe pain. The averages of the daily pelvic pain scores (cyclic and non-cyclic, combined) entered in participants' electronic diaries (eDiaries) were calculated for Baseline and Treatment Cycle 2 (approximately Week 4 to Week 8). A negative change indicates a decrease in pain severity from baseline.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Per protocol, this analysis included AEs reported up to 14 days after end of study intervention.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0, and after administration of the study drug on Day 56. The cough frequency is the coughs/hr over each 24 hour period. An independent cough monitoring core lab provided documentation of the time of each cough event over each 24-hour period. A negative change indicates a decrease in cough frequency, while a positive change indicates an increase in cough frequency.

Awake Objective Cough Frequency (per hour) was defined as the total number of cough events during the monitoring period (in general, 24-hr interval) while the participant was awake divided by the total duration (in hours) for the monitoring period that the participant was awake. 24 hour sound recordings were made at Baseline (Study Day -1) and at Week 12 (Day 84) using a digital recording device. An independent cough monitoring center documented the time of each cough event over the 24 hour period, as well as the time when the participant went to sleep and the time the participant woke. Least-squares (LS) mean change from baseline (in log scale) with associated standard error (SE) reported for each treatment group. Change from Baseline in Awake Objective Cough Frequency = (Post-Treatment Awake Cough Frequency minus Baseline Awake Cough Frequency).

The concentration of capsaicin inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of capsaicin for cough challenge were 0.3 micromoles (µM), 1 µM, 3 µM, 10 µM, 30 µM, 100 µM, 300 µM, and 1000 µM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of capsaicin with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

The concentration of citric acid inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of citric acid for cough challenge were 1 millimoles (mM), 3 mM, 10 mM, 30 mM, 100 mM, 300 mM, 1 M, and 3 M. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of citric acid with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

The concentration of ATP inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of ATP for cough challenge were 0.1 mM, 0.3 mM, 1 mM, 3 mM, 10 mM, 30 mM, 100 mM, and 300 mM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of ATP with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

The concentration of distilled water inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of distilled water for cough challenge were 20%, 40%, 60%, 80%, and 100%. The Measure Type is least-squares mean in natural log scale. The number of coughs generated in 1 minute of exposure was recorded. The challenge agent was prepared by dilution of distilled water with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the results of the 2-period cross-over study. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. A negative change indicates a decrease in cough frequency, while a positive change indicates an increase in cough frequency.

Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period.

Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. A negative value indicates a decrease in cough frequency.

Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Percent change from baseline in awake objective cough frequency (0-6 hours after the morning dose) was reported at each dosing interval. Percent change in awake cough frequency = 100 X (post treatment cough frequency - baseline cough frequency) divided by the baseline cough frequency. A negative value indicates a decrease in cough frequency.

BP data will be summarized using descriptive statistics

The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with capsaicin was assessed in male and female healthy participants and participants with chronic cough. Capsaicin-evoked cough challenge was performed 2 hours post-dose in Periods 1 and 2. The maximal cough response (Emax) to capsaicin was assessed. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation. The number of explosive cough sounds occurring within the first 15 seconds after inhalation were recorded. Nonlinear mixed-effects modeling was used to estimate the Emax. Population pharmacodynamic modeling was performed in NONMEM 7.3. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.

The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with capsaicin was assessed in male and female healthy participants and participants with chronic cough. Capsaicin-evoked cough challenge was performed 2 hours post-dose in Periods 1 and 2. The concentration of capsaicin required to induce 50% of the Emax (ED50) was assessed. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation. Nonlinear mixed-effects modeling was used to estimate the ED50. Population pharmacodynamic modeling was performed in NONMEM 7.3 using Laplace estimation method. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.

Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.

Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.

Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.

Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.

The provocative concentration (PC) of inhaled methacholine required to reduce forced expiratory volume in 1 second (FEV1) by 20% (PC20) was calculated from the methacholine challenge at screening and 2 hours (+15 minutes) post dose on Day 3 of each Treatment Period using a five-breath dosimeter method. The primary endpoint was the methacholine PC20 value normalized by means of a log (base 2) transformation, at 2 dose levels compared with placebo in participants with asthma following provocation with methacholine.

Subjects were instructed to select a number on a scale that best described their knee arthritis pain during the past 24 hours. The scale was between 0 and 10 where 0 was no pain and 10 was the worst possible pain. The scale was completed by telephone (an interactive voice response system \[IVRS\]) every evening before bedtime.

Daytime Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participants is awake. 24-hour sound recordings were collected using a digital recording device. Change from baseline in awake cough frequency = (post-treatment awake cough frequency - baseline awake cough frequency). A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

The apnea-hypopnea index (AHI) is the sum of the apnea and hypopnea indices for each participant. The apnea index for each participant is calculated as the number of apneas divided by the total sleep time. The hypopnea index for each participant is calculated as the number of hypopneas divided by the total sleep time. These measurements are collected from polysonagraphs (PSGs), which are diagnostic sleep studies that collect electroencephalogram (EEG), electrooculograph (EOG), electromyogram (EMG), electrocardiogram (ECG), airflow, respiratory effort, oximetry, and sleep position data. Baseline AHI measurements in each period are obtained on Day -1. Individual AHI fold-change from baseline in each treatment period are calculated as the ratio of on-treatment AHI to baseline AHI.

The mean area under the concentration-time curve from time 0 to infinity (AUC0-inf) of plasma gefapixant was assessed. In Part 1, participants with Moderate RI, Severe RI, or normal renal function (i. e., Healthy Controls) received a single oral dose of gefapixant 50 mg at Hour 0 on Day 1. In Part 2, Period 1, ESRD participants received a single oral dose of gefapixant 50 mg at Hour 0 on Day 1, immediately following the scheduled HD. In Part 2, Period 2, participants received a single oral dose of gefapixant 50 mg at Hour 0 on Day 1, approximately 2 hours prior to initiation of HD. Non-model based summary statistics were provided for the number of participants with non-missing data, as well as mean and standard deviation values. Serial blood samples for the determination of plasma gefapixant concentrations were collected at predose and at selected time points over 72 hours postdose.

To evaluate the extent of gefapixant removal by hemodialysis, individual values of AUC0-inf, were natural log (ln)-transformed and analyzed using a linear mixed-effects model with population (ESRD Non-HD, ESRD HD) as a fixed effect. An unstructured covariance matrix was used to allow for unequal variances and to model the correlation between the 2 measurements within each participant. A two-sided 90% confidence interval (CI) for the true difference in means was calculated for AUC0-inf. These confidence limits were exponentiated to obtain the 90% CI for the geometric least squares mean ratio (GMR) (ESRD HD/ESRD Non-HD) for AUC0-inf.

AUC0-inf values of plasma gefapixant based on BSA-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of AUC0-inf were natural log-transformed and evaluated with a linear fixed-effects model containing BSA-normalized eGFR as a continuous variable. The back transformed mean AUC0-inf and corresponding 95% CI were predicted at the midpoint of the BSA enormalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their normalized eGFR estimates were predicted at midpoint 75 mL/min.

AUC0-inf values of plasma gefapixant based on BSA non-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of AUC0-inf were natural log-transformed and evaluated with a linear fixed-effects model containing BSA non-normalized eGFR as a continuous variable. The back transformed mean AUC0-inf and corresponding 95% CI were predicted at the midpoint of the BSA non-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their BSA non-normalized eGFR estimates were predicted at midpoint 75 mL/min.

Geometric mean and 95%CI for AUC0-inf were estimated in participants with moderate RI, severe RI, ESRD requiring but not receiving HD, and normal renal function (i. e., Healthy Controls). Individual values of AUC0-inf, were ln-transformed and evaluated with a linear fixed-effects heterogeneous variance model containing a categorical effect for population (ESRD Non-HD, severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). To compare subjects with RI in each of the renal categories to subjects with normal renal function, a two-sided 90% CI for the true difference in means (renal impairment - normal renal function) was calculated for AUC0-inf, using the mean square error from the model and referencing a t-distribution. For each of the RI populations, these confidence limits were exponentiated to obtain the 90% CI for the GMR (renal impairment/normal renal function).

The mean area under the concentration-time curve from time 0 to the last quantifiable sample (AUC0-last), above the lower limit of quantitation (LLOQ), of plasma gefapixant in participants with moderate RI, severe RI, ESRD, or normal renal function (i. e., Healthy Controls) was assessed. Non-model based summary statistics were provided for the number of participants with non-missing data, as well as mean and standard deviation values.

To evaluate the extent of gefapixant removal by hemodialysis, individual values of AUC0-last, were ln-transformed and analyzed using a linear mixed-effects model with population (ESRD Non-HD, ESRD HD) as a fixed effect. An unstructured covariance matrix was used to allow for unequal variances and to model the correlation between the 2 measurements within each participant. A two-sided 90% CI for the true difference in means was calculated for AUC0-last. These confidence limits were exponentiated to obtain the 90% CI for the geometric least squares mean ratio (GMR) (ESRD HD/ESRD Non-HD) for AUC0-last.

AUC0-last values of plasma gefapixant based on BSA-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of AUC0last were natural log-transformed and evaluated with a linear fixed-effects model containing BSA-normalized eGFR as a continuous variable. The mean AUC0-ilast and corresponding 95% CI were back-transformed and predicted at the midpoint of th BSA enormalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their normalized eGFR estimates were predicted at midpoint 75 mL/min.

AUC0-last values of plasma gefapixant based on BSA non-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of AUC0-last were natural log-transformed and evaluated with a linear fixed-effects model containing BSA non-normalized eGFR as a continuous variable. The back transformed mean AUC0-last and corresponding 95% CI were predicted at the midpoint of the BSA non-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their BSA non-normalized eGFR estimates were predicted at midpoint 75 mL/min.

Geometric mean and 95%CI for AUC0-last were estimated in participants with moderate RI, severe RI, ESRD requiring but not receiving HD, and normal renal function (i. e., Healthy Controls). Individual values of AUC0-last, were ln-transformed and evaluated with a linear fixed-effects heterogeneous variance model containing a categorical effect for population (ESRD Non-HD, severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). To compare subjects with RI in each of the renal categories to subjects with normal renal function, a two-sided 90% CI for the true difference in means (renal impairment - normal renal function) was calculated for AUC0-last, using the mean square error from the model and referencing a t-distribution. For each of the RI populations, these confidence limits were exponentiated to obtain the 90% CI for the GMR (renal impairment/normal renal function).

The maximum concentration (Cmax) of plasma gefapixant in participants with moderate RI, severe RI, ESRD Non-HD, ESRD HD, or normal renal function (i. e., Healthy Controls) following administration of gefapixant 50 mg was assessed. Non-model based summary statistics were provided for the number of participants with non-missing data, as well as mean and standard deviation values. Serial blood samples for the determination of plasma gefapixant concentrations were collected at predose and at selected time points over 72 hours postdose.

To evaluate the extent of gefapixant removal by hemodialysis, individual values of Cmax, were ln transformed and analyzed using a linear mixed-effects model with population (ESRD Non-HD, ESRD HD) as a fixed effect. An unstructured covariance matrix was used to allow for unequal variances and to model the correlation between the 2 measurements within each participant. A two-sided 90% CI for the true difference in means was calculated for Cmax. These confidence limits were exponentiated to obtain the 90% CI for the geometric least squares mean ratio (GMR) (ESRD HD/ESRD Non-HD) for Cmax.

Cmax values of plasma gefapixant based on BSA-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of Cmax were natural log-transformed and evaluated with a linear fixed-effects model containing BSA-normalized eGFR as a continuous variable. The back transformed mean Cmax and corresponding 95% CI were predicted at the midpoint of the BSA enormalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their normalized eGFR estimates were predicted at midpoint 75 mL/min. Serial blood samples for the determination of plasma gefapixant concentrations were collected at predose and at selected time points over 72 hours postdose.

Cmax values of plasma gefapixant based on BSA non-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of Cmax were natural log-transformed and evaluated with a linear fixed-effects model containing BSA non-normalized eGFR as a continuous variable. The back transformed mean Cmax and corresponding 95% CI were predicted at the midpoint of the BSA non-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their BSA non-normalized eGFR estimates were predicted at midpoint 75 mL/min. Serial blood samples for the determination of plasma gefapixant concentrations were collected at predose and at selected time points over 72 hours postdose.

Geometric mean and 95%CI for Cmax were estimated in participants with moderate RI, severe RI, ESRD requiring but not receiving HD, and normal renal function (i. e., Healthy Controls). Individual values of Cmax, were ln-transformed and evaluated with a linear fixed-effects heterogeneous variance model containing a categorical effect for population (ESRD Non-HD, severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). To compare subjects with RI in each of the renal categories to subjects with normal renal function, a two-sided 90% CI for the true difference in means (renal impairment - normal renal function) was calculated for Cmax, using the mean square error from the model and referencing a t-distribution. For each of the RI populations, these confidence limits were exponentiated to obtain the 90% CI for the GMR (renal impairment/normal renal function).

The apparent clearance (CL/F) of plasma gefapixant after oral administration of gefapixant 50 mg in participants with moderate RI, severe RI, ESRD requiring HD, or normal renal function (i. e., Healthy Controls) was assessed. Non-model based summary statistics were provided for the number of participants with non-missing data, as well as mean and standard deviation values. Serial blood samples for the determination of plasma gefapixant concentrations were collected at predose and at selected time points over 72 hours postdose.

To evaluate the extent of gefapixant removal by hemodialysis, individual values of CL/F, were ln-transformed and analyzed using a linear mixed-effects model with population (ESRD Non-HD, ESRD HD) as a fixed effect. An unstructured covariance matrix was used to allow for unequal variances and to model the correlation between the 2 measurements within each participant. A two-sided 90% CI for the true difference in means was calculated for CL/F. These confidence limits were exponentiated to obtain the 90% CI for the geometric least squares mean ratio (GMR) (ESRD HD/ESRD Non-HD) for CL/F.

CL/F values of plasma gefapixant based on BSA-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of CL/F were natural log-transformed and evaluated with a linear fixed-effects model containing BSA-normalized eGFR as a continuous variable. The back transformed mean CL/F and corresponding 95% CI were predicted at the midpoint of the BSA enormalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their normalized eGFR estimates were predicted at midpoint 75 mL/min.

CL/F values of plasma gefapixant based on BSA non-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of CL/F were natural log-transformed and evaluated with a linear fixed-effects model containing BSA non-normalized eGFR as a continuous variable. The back transformed mean CL/F and corresponding 95% CI were predicted at the midpoint of the BSA non-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their BSA non-normalized eGFR estimates were predicted at midpoint 75 mL/min.

Geometric mean and 95% CI for CL/F were estimated in participants with moderate RI, severe RI, ESRD requiring but not receiving HD, and normal renal function (i. e., Healthy Controls). Individual values of CL/F, were ln-transformed and evaluated with a linear fixed-effects heterogeneous variance model containing a categorical effect for population (ESRD Non-HD, severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). To compare subjects with RI in each of the renal categories to subjects with normal renal function, a two-sided 90% CI for the true difference in means (renal impairment - normal renal function) was calculated for CL/F, using the mean square error from the model and referencing a t-distribution. For each of the RI populations, these confidence limits were exponentiated to obtain the 90% CI for the GMR (renal impairment/normal renal function).

The renal clearance (CLr) in participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) was assessed. Non-model base summary statistics were provided. Renal clearance could not be assessed for participants with ESRD. Urine specimens were obtained by spot collection predose and at multiple timepoints postdose.

Geometric mean and 95% CI for CLr were estimated in participants with moderate RI, severe RI, and normal renal function (i. e., Healthy Controls). Individual values of CLr, were ln-transformed and evaluated with a linear fixed-effects heterogeneous variance model containing a categorical effect for population (severe RI, moderate RI, and healthy matched control, based on BSA normalized eGFR). To compare subjects with RI in each of the renal categories to subjects with normal renal function, a two-sided 90% CI for the true difference in means (renal impairment - normal renal function) was calculated for CLr, using the mean square error from the model and referencing a t-distribution. For each of the RI populations, these confidence limits were exponentiated to obtain the 90% CI for the GMR (renal impairment/normal renal function).

CLr values of plasma gefapixant based on BSA-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of CLr were natural log-transformed and evaluated with a linear fixed-effects model containing BSA-normalized eGFR as a continuous variable. The back transformed mean CLr and corresponding 95% CI were predicted at the midpoint of the BSA-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their normalized eGFR estimates were predicted at midpoint 75 mL/min.

CLr values of plasma gefapixant based on BSA non-normalized eGFR for participants with moderate RI, severe RI, or normal renal function (i. e., Healthy Controls) were estimated using regression analysis. Individual values of CLr were natural log-transformed and evaluated with a linear fixed-effects model containing BSA non-normalized eGFR as a continuous variable. The back transformed mean AUC0-inf and corresponding 95% CI were predicted at the midpoint of the BSA non-normalized eGFR range for each group (45 mL/min, 22.5 mL/min, and 139 mL/min for moderate RI, severe RI, and healthy controls, respectively). Although no participants with mild RI were included in this study, their BSA non-normalized eGFR estimates were predicted at midpoint 75 mL/min.

Plasma gefapixant concentration versus time profiles will be plotted for each subject; similar summary plots will be constructed for each treatment period. Plasma gefapixant PK parameters will be calculated using noncompartmental methods and summarized using descriptive statistics by each treatment.

Analysis of variance (ANOVA) will be performed on log normal-transformed Cmax and AUC0-t values to determine the extent of a drug interaction, if any, of Omeprazole on the plasma gefapixant PK parameters

Plasma gefapixant concentration versus time profiles will be plotted for each subject; similar summary plots will be constructed for each treatment period. Plasma gefapixant PK parameters will be calculated using noncompartmental methods and summarized using descriptive statistics by each treatment.

Analysis of variance (ANOVA) will be performed on log normal-transformed Cmax and AUC0-t values to determine the extent of a drug interaction, if any, of omeprazole on the plasma gefapixant PK parameters.

Analysis of variance (ANOVA) will be performed on log normal-transformed Cmax and AUC0-t values to determine the extent of a drug interaction, if any, of omeprazole on the plasma gefapixant PK parameters. These analyses will be conducted for both fed and fasted conditions and the 50 mg and 150 mg treatments.