A Dose Escalation Study of Gefapixant (AF-219/MK-7264) in Refractory Chronic Cough (MK-7264-010)

Sponsor

Afferent Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02349425

Collaborator

(none)

Enrollment

Arms

11.1

Actual Duration (Months)

Study Details

Study Description

Brief Summary

A randomized, double-blind, placebo-controlled, crossover, dose escalation study to assess the efficacy and tolerability of gefapixant (AF-219; MK-7264) in participants with refractory chronic cough.

Condition or Disease	Intervention/Treatment	Phase
Refractory Chronic Cough	Drug: Gefapixant Drug: Placebo (for gefapixant)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

59 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects With Refractory Chronic Cough

Actual Study Start Date :

Mar 9, 2015

Actual Primary Completion Date :

Feb 1, 2016

Actual Study Completion Date :

Feb 9, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Gefapixant>Placebo 50, 100, 150, and 200 mg gefapixant twice daily (BID) for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.	Drug: Gefapixant Gefapixant 7.5 and 50mg tablets administered orally Other Names: AF-219 MK-7264 Drug: Placebo (for gefapixant) Placebo to gefapixant 7.5 and 50mg tablets administered orally
Experimental: Cohort 1: Placebo>Gefapixant Placebo BID for 16 days in Period 1 and gefapixant 50, 100, 150, and 200 mg BID for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.	Drug: Gefapixant Gefapixant 7.5 and 50mg tablets administered orally Other Names: AF-219 MK-7264 Drug: Placebo (for gefapixant) Placebo to gefapixant 7.5 and 50mg tablets administered orally
Experimental: Cohort 2: Gefapixant>Placebo Gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.	Drug: Gefapixant Gefapixant 7.5 and 50mg tablets administered orally Other Names: AF-219 MK-7264 Drug: Placebo (for gefapixant) Placebo to gefapixant 7.5 and 50mg tablets administered orally
Experimental: Cohort 2: Placebo>Gefapixant Placebo BID for 16 days in Period 1 and gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.	Drug: Gefapixant Gefapixant 7.5 and 50mg tablets administered orally Other Names: AF-219 MK-7264 Drug: Placebo (for gefapixant) Placebo to gefapixant 7.5 and 50mg tablets administered orally

Outcome Measures

Primary Outcome Measures

Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.
Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.
Percent Change From Baseline in Awake Cough Frequency for Cohort 1 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.
Percent Change From Baseline in Awake Cough Frequency for Cohort 2 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.
Responder Analysis of Awake Cough Frequency for Cohort 1 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.
Responder Analysis of Awake Cough Frequency for Cohort 2 [Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
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.

Secondary Outcome Measures

Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1 [Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses]
Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2 [Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses]
Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1 [Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses]
Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2 [Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses]
Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline in Sleep Cough Frequency - Cohort 1 [Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline in Sleep Cough Frequency - Cohort 2 [Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses]
Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 [Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39]
The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2 [Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39]
The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2 [Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39]
The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. Participants' perception of their cough severity was assessed, based on the LCQ-Acute score, at Baseline and last day of dose. LCQ was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1 [Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39]
Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2 [Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39]
Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.

Other Outcome Measures

Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2 [24 hours (while awake) on Days 0 and 22 (Baseline)]
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. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) Awake (0 - 8 Hours) Cough Frequency for Cohort 1 and Cohort 2 [First 8 hours (while awake) on Days 0 and 22 (Baseline)]
Awake (0 - 8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24 hour sound recordings were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2 [24 hours (while awake) on Days 0 and 22 (Baseline)]
Total (0 - 24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours) for the monitoring period. 24 hour sound recordings were collected using a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) for Sleep Cough Frequency for Cohort 1 and Cohort 2 [First 8 hours (while asleep) on Days 0 and 22 (Baseline)]
Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) for the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 and Cohort 2 [Baseline (Days 0 and 22)]
The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) for the Acute Leicester Cough Questionnaire (LCQ) Instrument for Cohort 1 and Cohort 2 [Days 0 and 22 (Baseline)]
The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. As per the Statistical Analysis Plan, each domain and total LCQ score change from baseline were analyzed without the treatment by dose interaction. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Baseline (Predose) for Cough Visual Analogue Scale (VAS) for Cohort 1 and Cohort 2 [Screening, Days 0 and 22 (Baseline)]
Cough VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 (no cough) and 100 (most severe cough) mm. Baseline cough VAS is defined as average of screening and baseline cough VAS. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Chest radiograph or computed tomography (CT) thorax within the last 12 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough
Refractory chronic cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip or unexplained cough: a cough for which no objective evidence of an underlying trigger can be determined after investigation
Score of ≥ 40 mm on the Cough Severity Visual Analog Scale (VAS) at Screening
Women of child-bearing potential must use 2 forms of acceptable birth control method from Screening through the Follow-Up Visit.
Male participants and their partners of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug.
Written informed consent.
Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

Current smoker
Individuals who have given up smoking within the past 6 months, or those with >20 pack-year smoking history
Treatment with an angiotensin converting enzyme (ACE)-inhibitor as the potential cause of a participant's cough, or requiring treatment with an ACE-inhibitor during the study or within 4 weeks prior to the Baseline Visit (Day 0)
Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 60%
History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0)
History of opioid use within 1 week of the Baseline Visit (Day 0)
Requiring concomitant therapy with prohibited medications
Body mass index (BMI) <18 kg/m^{2 or ≥ 37 kg/m}2
History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including participants with <3 excised basal cell carcinomas)
History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years
Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection)
Screening systolic blood pressure (SBP) >160 mmHg or a diastolic blood pressure (DBP)

90 mmHg

Clinically significant abnormal electrocardiogram (ECG) at Screening
Personal or family history of congenital long QT syndrome or family history of sudden death
Cardiac pacemaker
Significantly abnormal laboratory tests at Screening
Breastfeeding
Treatment with an investigational drug (except gefapixant) or biologic within 60 days preceding the first dose of study medication or plans to take another investigational drug or biologic within 30 days of study completion
Blood donation within 56 days or plasma donation within 7 days prior to dosing
Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Afferent Pharmaceuticals, Inc.

Investigators

Study Director: Medical Director, Afferent Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

P2X3 Receptor Antagonist (AF-219) in Refractory Chronic Cough: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Study

Publications

None provided.

Responsible Party:

Afferent Pharmaceuticals, Inc.

ClinicalTrials.gov Identifier:

NCT02349425

Other Study ID Numbers:

7264-010
AF219-010
MK-7264-010
2015-000474-35

First Posted:

Jan 28, 2015

Last Update Posted:

Oct 22, 2020

Last Verified:

Sep 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Cough

Study Results

Participant Flow

Recruitment Details	Participants were recruited at 12 clinical trial sites in the United States.
Pre-assignment Detail	29 participants were enrolled, randomized and treated with study drug in Cohort 1 and 30 participants in Cohort 2. Of the 30 participants in Cohort 2, 18 of them were from Cohort 1 and they re-consented, were given new randomization numbers and treated with study drug.

Arm/Group Title	Cohort 1: Gefapixant>Placebo	Cohort 1: Placebo>Gefapixant	Cohort 2: Gefapixant>Placebo	Cohort 2: Placebo>Gefapixant
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.	Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.	Gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.	Placebo to gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth twice daily for 4 days each in Period 1 and gefapixant 7.5, 15, 30, and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2 there was a 14-21 day washout period between treatment periods.
Period Title: Period 1
STARTED	15	14	15	15
COMPLETED	14	13	15	15
NOT COMPLETED	1	1	0	0
Period Title: Period 1
STARTED	14	13	15	15
COMPLETED	14	12	14	15
NOT COMPLETED	0	1	1	0

Baseline Characteristics

Arm/Group Title	Cohort 1 - Gefapixant>Placebo	Cohort 1 - Placebo>Gefalixant	Cohort 2 - Gefapixant>Placebo	Cohort 2 - Placebo>Gefapixant	Total
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7-day washout period between treatment periods.	Placebo to gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 50, 100, 150, and 200 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.	Gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and placebo to gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2, there was a 14 to 21-day washout period between treatment periods.	Placebo to gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 1 and gefapixant 7.5, 15, 30 and 50 mg, tablet(s) administered by mouth, twice daily, for 4 days each in Period 2. For Cohort 2, there was a 14 to 21-day washout period between treatment periods.	Total of all reporting groups
Overall Participants	15	14	15	15	59
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.5 (6.92)	61.7 (7.77)	60.7 (9.42)	59.8 (12.8)	61.7 (9.45)
Sex: Female, Male (Count of Participants)
Female	13 86.7%	12 85.7%	12 80%	12 80%	49 83.1%
Male	2 13.3%	2 14.3%	3 20%	3 20%	10 16.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 6.7%	0 0%	1 6.7%	1 6.7%	3 5.1%
Not Hispanic or Latino	14 93.3%	14 100%	14 93.3%	14 93.3%	56 94.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 7.1%	1 6.7%	0 0%	2 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 6.7%	0 0%	1 1.7%
White	15 100%	13 92.9%	13 86.7%	15 100%	56 94.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	26	25	24	25	23	22	25	25
Geometric Mean (95% Confidence Interval) [Log coughs/hour]	0.56	0.95	0.46	0.95	0.48	0.90	0.45	1.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0055
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-41.222
	Confidence Interval	(2-Sided) 95% -59.294 to -15.127
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-51.973
	Confidence Interval	(2-Sided) 95% -68.230 to -27.397
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0075
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-46.853
	Confidence Interval	(2-Sided) 95% -66.291 to -16.206
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-57.067
	Confidence Interval	(2-Sided) 95% -73.375 to -30.771
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

2. Primary Outcome

Title	Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	29	27
Geometric Mean (95% Confidence Interval) [Log coughs/hour]	0.80	0.93	0.67	0.90	0.53	0.84	0.44	1.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2542
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-14.691
	Confidence Interval	(2-Sided) 95% -35.307 to 12.493
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0267
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-25.165
	Confidence Interval	(2-Sided) 95% -42.014 to -3.4210
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0198
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-37.146
	Confidence Interval	(2-Sided) 95% -57.345 to -7.3821
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model which uses log-transformation.

Method of Estimation	Estimation Parameter	Estimated percent change
	Estimated Value	-55.920
	Confidence Interval	(2-Sided) 95% -71.923 to -30.797
	Parameter Dispersion	Type: Value:
	Estimation Comments	Percent change difference between Gefapixant and placebo was estimated by 100 x [e^diff - 1] where e=exponent of difference; and diff = the treatment mean difference from mixed model of change from baseline based on log-transformed data.

3. Primary Outcome

Title	Percent Change From Baseline in Awake Cough Frequency for Cohort 1
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1' - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	26	25	24	25	23	22	25	25
Mean (Standard Deviation) [Percent Change]	-20.6 (84.29)	-0.1 (33.75)	-31.7 (70.27)	1.9 (35.18)	-22.0 (82.84)	-0.1 (39.55)	-27.9 (57.03)	15.1 (48.38)

4. Primary Outcome

Title	Percent Change From Baseline in Awake Cough Frequency for Cohort 2
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	29	27
Mean (Standard Deviation) [Percent Change]	5.0 (125.05)	-3.8 (36.13)	-21.4 (39.32)	-6.4 (33.78)	-26.3 (61.01)	-1.1 (64.38)	-28.1 (74.90)	23.1 (92.60)

5. Primary Outcome

Title	Responder Analysis of Awake Cough Frequency for Cohort 1
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	26	25	24	25	23	22	25	25
% Reduction ≥70	34.6	0	33.3	0	34.8	4.5	32.0	0
% Reduction ≥50	46.2	0	50.0	4.0	47.8	4.5	44.0	0
% Reduction ≥30	53.8	12.0	66.7	16.0	65.2	22.7	56.0	16.0

6. Primary Outcome

Title	Responder Analysis of Awake Cough Frequency for Cohort 2
Description	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.
Time Frame	Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	29	27
% Reduction ≥70	3.4	3.6	10.0	0	20.7	3.4	31.0	3.7
% Reduction ≥50	13.8	7.1	20.0	6.9	31.0	17.2	41.4	11.1
% Reduction ≥30	37.9	14.3	46.7	20.7	62.1	31.0	55.2	22.2

7. Secondary Outcome

Title	Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1
Description	Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	26	25	24	25	23	22	25	25
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	-24.5	-5.5	-24.5	-0.1	-26.5	2.7	-27.5	2.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.0
	Confidence Interval	(2-Sided) 95% -31.2 to -6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.4
	Confidence Interval	(2-Sided) 95% -36.7 to -12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments	Per protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-29.3
	Confidence Interval	(2-Sided) 95% -49.0 to -9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-29.6
	Confidence Interval	(2-Sided) 95% -44.6 to -14.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2
Description	Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	29	27
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	-8.0	-1.1	-15.2	-1.7	-21.7	8.5	-21.9	4.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.332
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.9
	Confidence Interval	(2-Sided) 95% -21.0 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.5
	Confidence Interval	(2-Sided) 95% -23.3 to -3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-30.2
	Confidence Interval	(2-Sided) 95% -44.7 to -15.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-26.7
	Confidence Interval	(2-Sided) 95% -42.3 to -11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1
Description	Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	26	25	24	25	23	22	25	25
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	-16.6	-1.5	-17.6	-0.9	-18.0	1.5	-17.4	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.2
	Confidence Interval	(2-Sided) 95% -23.5 to -6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.7
	Confidence Interval	(2-Sided) 95% -26.1 to -7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.5
	Confidence Interval	(2-Sided) 95% -31.1 to -7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.5
	Confidence Interval	(2-Sided) 95% -31.8 to -9.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2
Description	Total (0-24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	29	27
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	-6.9	-2.7	-11.0	-3.8	-16.9	1.4	-15.9	1.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.315
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95% -12.3 to 4.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.2
	Confidence Interval	(2-Sided) 95% -13.7 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.2
	Confidence Interval	(2-Sided) 95% -27.4 to -9.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.6
	Confidence Interval	(2-Sided) 95% -26.3 to -9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in Sleep Cough Frequency - Cohort 1
Description	Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	24	24	21	24	22	22	24	25
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	-3.5	0.1	-3.1	-0.7	-2.0	-0.1	-3.6	0.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.169
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95% -8.6 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.341
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95% -7.5 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.311
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95% -5.8 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.128
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95% -8.6 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in Sleep Cough Frequency - Cohort 2
Description	Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 2 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days. .	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	29	28	30	29	29	29	28	27
Least Squares Mean (95% Confidence Interval) [Coughs/hour]	0.6	-0.6	-3.1	-2.5	-2.4	-1.6	-3.0	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.613
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95% -3.5 to 5.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	.743
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -4.3 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.589
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95% -4.1 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.205
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95% -13.2 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1
Description	The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	27	27	26	27	26	27	28	28
Least Squares Mean (95% Confidence Interval) [Score on a scale]	-0.6	0.0	-1.1	0.1	-1.5	0.1	-1.6	0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0811
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -1.4 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0097
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95% -2.2 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95% -2.6 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0050
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95% -2.8 to -0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2
Description	The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 1 - Placebo for Gefapixant 15 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days. .	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	30	29	30	29	30	29	29	29
Least Squares Mean (95% Confidence Interval) [Score on a scale]	-1.0	-0.3	-1.2	-0.3	-1.7	-0.3	-1.6	-0.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0506
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95% -1.4 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0447
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95% -1.7 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0026
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95% -2.2 to -0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0405
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95% -2.2 to -0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2
Description	The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. Participants' perception of their cough severity was assessed, based on the LCQ-Acute score, at Baseline and last day of dose. LCQ was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	27	28	30	29
Least Squares Mean (95% Confidence Interval) [Score on a scale]	3.02	-0.82	3.57	0.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.84
	Confidence Interval	(2-Sided) 95% 1.88 to 5.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.52
	Confidence Interval	(2-Sided) 95% 1.66 to 5.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1
Description	Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 1 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 1 - Gefapixant 50 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 1 - Gefapixant 100 mg	Cohort 1 - Placebo for Gefapixant 100 mg	Cohort 1 - Gefapixant 150 mg	Cohort 1 - Placebo for Gefapixant 150 mg	Cohort 1 - Gefapixant 200 mg	Cohort 1 - Placebo for Gefapixant 200 mg
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 100 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 150 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 200 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.
Measure Participants	27	28	27	27	26	27	26	27
Least Squares Mean (95% Confidence Interval) [Score on a scale]	-14.4	-3.8	-26.3	-6.3	-28.8	-2.6	-31.5	2.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.096
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.6
	Confidence Interval	(2-Sided) 95% -23.2 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.0
	Confidence Interval	(2-Sided) 95% -33.6 to -6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-26.1
	Confidence Interval	(2-Sided) 95% -40.7 to -11.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-33.8
	Confidence Interval	(2-Sided) 95% -48.4 to -19.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2
Description	Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity. Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Time Frame	Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all participants in Cohort 2 for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm/Group Title	Cohort 2 - Gefapixant 7.5 mg	Cohort 2 - Placebo for Gefapixant 7.5 mg	Cohort 2 - Gefapixant 15 mg	Cohort 1 - Placebo for Gefapixant 50 mg	Cohort 2 - Gefapixant 30 mg	Cohort 2 - Placebo for Gefapixant 30 mg	Cohort 2 - Gefapixant 50 mg	Cohort 2 - Placebo for Gefapixant 50 mg
Arm/Group Description	Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days. .	Gefapixant 15 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 30 mg tablet administered by mouth BID for 4 days.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 50 mg tablet administered by mouth BID for 4 days.	Placebo tablets administered by mouth BID for 4 days.
Measure Participants	30	29	30	29	30	29	29	29
Least Squares Mean (95% Confidence Interval) [Score on a scale]	-12.6	-6.2	-17.4	-10.0	-23.3	-7.7	-24.7	-9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 50 mg, Cohort 1 - Placebo for Gefapixant 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.311
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.4
	Confidence Interval	(2-Sided) 95% -19.1 to 6.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 100 mg, Cohort 1 - Placebo for Gefapixant 100 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.232
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.4
	Confidence Interval	(2-Sided) 95% -19.7 to 4.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 150 mg, Cohort 1 - Placebo for Gefapixant 150 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.6
	Confidence Interval	(2-Sided) 95% -27.6 to -3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort 1 - Gefapixant 200 mg, Cohort 1 - Placebo for Gefapixant 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	Mixed Models Analysis
	Comments	Per Protocol, statistical analysis follows a Mixed Model.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.4
	Confidence Interval	(2-Sided) 95% -30.4 to -0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Other Pre-specified Outcome

Title	Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2
Description	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. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	24 hours (while awake) on Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	28	26	30	29
Mean (Standard Deviation) [Coughs/hour]	54.5 (41.09)	52.8 (40.44)	49.6 (44.01)	46.1 (39.82)

19. Other Pre-specified Outcome

Title	Baseline (Predose) Awake (0 - 8 Hours) Cough Frequency for Cohort 1 and Cohort 2
Description	Awake (0 - 8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24 hour sound recordings were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	First 8 hours (while awake) on Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	28	26	30	29
Mean (Standard Deviation) [Coughs/hour]	51.8 (41.09)	53.3 (42.30)	47.2 (42.09)	42.2 (39.42)

20. Other Pre-specified Outcome

Title	Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2
Description	Total (0 - 24 hours) Objective Cough Frequency is the total number of cough events during the monitoring period divided by the total duration (in hours) for the monitoring period. 24 hour sound recordings were collected using a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	24 hours (while awake) on Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	28	26	30	29
Mean (Standard Deviation) [Coughs/hour]	39.7 (28.38)	37.9 (27.46)	36.3 (32.28)	32.2 (27.97)

21. Other Pre-specified Outcome

Title	Baseline (Predose) for Sleep Cough Frequency for Cohort 1 and Cohort 2
Description	Sleep Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24-hour sound recording were collected with a digital recording device. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	First 8 hours (while asleep) on Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	27	26	30	29
Mean (Standard Deviation) [Coughs/hour]	8.3 (9.30)	7.8 (9.80)	10.1 (26.77)	5.6 (7.58)

22. Other Pre-specified Outcome

Title	Baseline (Predose) for the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 and Cohort 2
Description	The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Days 0 and 22)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	28	28	30	28
Mean (Standard Deviation) [Score on a scale]	4.2 (1.89)	3.7 (1.61)	4.5 (1.98)	4.5 (1.93)

23. Other Pre-specified Outcome

Title	Baseline (Predose) for the Acute Leicester Cough Questionnaire (LCQ) Instrument for Cohort 1 and Cohort 2
Description	The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. As per the Statistical Analysis Plan, each domain and total LCQ score change from baseline were analyzed without the treatment by dose interaction. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days each.
Measure Participants	28	28	30	29
Psychological Domain Score	3.8 (1.21)	4.1 (1.45)	3.9 (1.57)	4.1 (1.56)
Physical Domain Score	4.4 (0.99)	4.7 (1.06)	4.8 (1.19)	5.0 (1.00)
Social Domain Score	4.2 (1.22)	4.3 (1.21)	3.9 (1.57)	4.2 (1.57)
Total Acute Leicester Score	12.3 (3.13)	13.1 (3.41)	12.6 (4.04)	13.3 (3.81)

24. Other Pre-specified Outcome

Title	Baseline (Predose) for Cough Visual Analogue Scale (VAS) for Cohort 1 and Cohort 2
Description	Cough VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 (no cough) and 100 (most severe cough) mm. Baseline cough VAS is defined as average of screening and baseline cough VAS. Baseline measurements were not available by individual arm because baseline cough frequencies were measured before participants received the first dose of study drug. Baseline summaries were evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Screening, Days 0 and 22 (Baseline)

Outcome Measure Data

Analysis Population Description
Analysis population consisted of all randomized participants in Periods 1 and 2 who received at least 1 dose of study drug, were compliant with the study procedure and had available data.

Arm/Group Title	Cohort 1 - Gefapixant	Cohort 1 - Placebo	Cohort 2 - Gefapixant	Cohort 2 - Placebo
Arm/Group Description	Gefapixant 50, 100, 150, and 200 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by mouth BID for 4 days.	Gefapixant 7.5, 15, 30, and 50 mg tablet(s) administered by mouth BID for 4 days each.	Placebo tablet administered by BID daily for 4 days each.
Measure Participants	28	28	30	29
Mean (Standard Deviation) [Score on a scale]	58.4 (18.66)	52.2 (19.21)	54.5 (24.26)	57.2 (23.71)

Adverse Events

	Cohort 1: Gefapixant 50 mg		Cohort 1: Gefapixant 100 mg		Cohort 1 - Gefapixant 150 mg		Cohort 1: Gefapixant 200 mg		Cohort 1 - Placebo		Cohort 2 - Gefapixant 7.5 mg		Cohort 2 - Gefapixant 15 mg		Cohort 2 - Gefapixant 30 mg		Cohort 2 - Gefapixant 50 mg		Cohort 2- Placebo
Time Frame	Adverse event data collection is up to 11 weeks All-cause mortality is up to 22 weeks
Adverse Event Reporting Description	Analysis population consisted of all randomized participants who received at least 1 dose of study drug

Arm/Group Title	Cohort 1: Gefapixant 50 mg		Cohort 1: Gefapixant 100 mg		Cohort 1 - Gefapixant 150 mg		Cohort 1: Gefapixant 200 mg		Cohort 1 - Placebo		Cohort 2 - Gefapixant 7.5 mg		Cohort 2 - Gefapixant 15 mg		Cohort 2 - Gefapixant 30 mg		Cohort 2 - Gefapixant 50 mg		Cohort 2- Placebo
Arm/Group Description	Gefapixant 50 mg tablet administered by mouth twice daily (BID) for 4 days.		Gefapixant 100 mg tablet administered by mouth BID or 4 days.		Gefapixant 150 mg tablet administered by mouth BID for 4 days.		Gefapixant 200 mg tablet administered by mouth BID for 4 days.		Placebo tablet administered by mouth BID for 4 days each.		Gefapixant 7.5 mg tablet administered by mouth BID for 4 days.		Gefapixant 15 mg tablet administered by mouth BID for 4 days.		Gefapixant 30 mg tablet administered by mouth BID for 4 days.		Gefapixant 50 mg tablet administered by mouth BID for 4 days.		Placebo tablet administered by mouth BID for 4 days each.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)		0/26 (0%)		0/26 (0%)		0/28 (0%)		0/30 (0%)		0/30 (0%)		0/30 (0%)		0/30 (0%)		0/29 (0%)
Serious Adverse Events
	Cohort 1: Gefapixant 50 mg		Cohort 1: Gefapixant 100 mg		Cohort 1 - Gefapixant 150 mg		Cohort 1: Gefapixant 200 mg		Cohort 1 - Placebo		Cohort 2 - Gefapixant 7.5 mg		Cohort 2 - Gefapixant 15 mg		Cohort 2 - Gefapixant 30 mg		Cohort 2 - Gefapixant 50 mg		Cohort 2- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		1/28 (3.6%)		0/26 (0%)		0/26 (0%)		1/28 (3.6%)		0/30 (0%)		0/30 (0%)		0/30 (0%)		1/30 (3.3%)		0/29 (0%)
Investigations
Blood creatinine increased	0/28 (0%)	0	1/28 (3.6%)	1	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/28 (0%)	0	1/28 (3.6%)	1	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	1/28 (3.6%)	1	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	1/30 (3.3%)	1	0/29 (0%)	0
Presyncope	0/28 (0%)	0	1/28 (3.6%)	1	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1: Gefapixant 50 mg		Cohort 1: Gefapixant 100 mg		Cohort 1 - Gefapixant 150 mg		Cohort 1: Gefapixant 200 mg		Cohort 1 - Placebo		Cohort 2 - Gefapixant 7.5 mg		Cohort 2 - Gefapixant 15 mg		Cohort 2 - Gefapixant 30 mg		Cohort 2 - Gefapixant 50 mg		Cohort 2- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/28 (60.7%)		8/28 (28.6%)		4/26 (15.4%)		6/26 (23.1%)		4/28 (14.3%)		6/30 (20%)		1/30 (3.3%)		13/30 (43.3%)		9/30 (30%)		2/29 (6.9%)
Gastrointestinal disorders
Dry mouth	1/28 (3.6%)	1	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	1/30 (3.3%)	1	0/30 (0%)	0	2/29 (6.9%)	2
Hypoaesthesia oral	1/28 (3.6%)	1	2/28 (7.1%)	2	0/26 (0%)	0	1/26 (3.8%)	1	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	1/30 (3.3%)	1	0/30 (0%)	0	0/29 (0%)	0
Paraesthesia oral	2/28 (7.1%)	2	1/28 (3.6%)	1	0/26 (0%)	0	1/26 (3.8%)	1	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	2/30 (6.7%)	2	1/30 (3.3%)	1	0/29 (0%)	0
Infections and infestations
Rhinitis	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	1/28 (3.6%)	1	2/30 (6.7%)	2	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Upper respiratory tract infection	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	1/28 (3.6%)	1	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	4/30 (13.3%)	4	0/29 (0%)	0
Viral upper respiratory tract infection	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	2/28 (7.1%)	2	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Investigations
Urine output decreased	2/28 (7.1%)	3	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Musculoskeletal and connective tissue disorders
Flank pain	1/28 (3.6%)	1	0/28 (0%)	0	0/26 (0%)	0	2/26 (7.7%)	2	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Nervous system disorders
Ageusia	2/28 (7.1%)	2	0/28 (0%)	0	0/26 (0%)	0	1/26 (3.8%)	1	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	2/30 (6.7%)	2	0/29 (0%)	0
Dysgeusia	13/28 (46.4%)	13	6/28 (21.4%)	6	4/26 (15.4%)	4	1/26 (3.8%)	1	1/28 (3.6%)	1	2/30 (6.7%)	2	1/30 (3.3%)	1	12/30 (40%)	12	4/30 (13.3%)	4	0/29 (0%)	0
Hypogeusia	2/28 (7.1%)	2	2/28 (7.1%)	2	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal dryness	0/28 (0%)	0	0/28 (0%)	0	0/26 (0%)	0	0/26 (0%)	0	0/28 (0%)	0	2/30 (6.7%)	2	0/30 (0%)	0	0/30 (0%)	0	0/30 (0%)	0	0/29 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No data collected as part of this study will be utilized in any written work, including publications, without the written consent of sponsor.

Results Point of Contact

Name/Title	Senior Vice President, Global Clinical Development
Organization	Merck Sharp & Dohme Corp.
Phone	1-800-672-6372
Email	ClinicalTrialsDisclosure@merck.com

Responsible Party:

Afferent Pharmaceuticals, Inc.

ClinicalTrials.gov Identifier:

NCT02349425

Other Study ID Numbers:

7264-010
AF219-010
MK-7264-010
2015-000474-35

First Posted:

Jan 28, 2015

Last Update Posted:

Oct 22, 2020

Last Verified:

Sep 1, 2020