Effect of Gefapixant (AF-219/MK-7264) on Cough Reflex Sensitivity (MK-7264-015)

• Sponsor: Afferent Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02397460
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arms: 3
• Actual Duration (Months): 12.6
• Patients Per Site Per Month: 4

Study Details

Study Description

Brief Summary

The primary objective of this double-blind crossover study is to assess the effect of single doses of 50 mg and 300 mg gefapixant (AF-219/MK-7264) on cough reflex sensitivity to capsaicin in both healthy participants and participants with chronic cough. This study will also assess the effect of single doses of gefapixant on cough reflex sensitivity to adenosine triphosphate (ATP) in healthy participants and participants with chronic cough.

Condition or Disease	Intervention/Treatment	Phase
Refractory Chronic Cough	Drug: Gefapixant; Drug: Placebo	Phase 2

Detailed Description

Up to 30 participants (male and female) who meet all entry criteria will be randomly assigned to treatment with gefapixant or matching placebo.

There will be a Screening Period, a Baseline Visit (cough participants only), and four Treatment Periods, with a washout period between treatments. Participants will return after their last Treatment Visit for a Follow-up Visit.

At the Screening Visit and during the Treatment Periods, cough sensitivity will be measured by standard clinical methodology incorporating two cough challenges: 1) capsaicin; 2) ATP. The ATP challenge will only be performed during the study treatment period. The Baseline Visit (cough participants only) will occur prior to Treatment Period 1. Daytime cough monitoring will be performed at the Baseline Visit and during each of the four Treatment Periods (cough participants only).

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Study to Assess the Effect of AF-219 on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects
• Actual Study Start Date: Apr 29, 2015
• Actual Primary Completion Date: Apr 22, 2016
• Actual Study Completion Date: May 16, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gefapixant 50 mg Gefapixant 50 mg (1 tablet) administered as a single dose	Drug: Gefapixant; Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets); Other Names: AF-219 MK-7264
Experimental: Gefapixant 300 mg Gefapixant 300 mg (6 tablets) administered as a single dose	Drug: Gefapixant; Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets); Other Names: AF-219 MK-7264
Placebo Comparator: Placebo Placebo-matching tablets administered as a single dose	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax) [2 hours post-dose]

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

2. Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50) [2 hours post-dose]

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

Secondary Outcome Measures

1. Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax) [2 hours post-dose]

   The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with adenosine triphosphate (ATP) was assessed in male and female healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 μmol/mL to 929 μmol/mL were prepared from ATP powder dissolved in saline, and were administered by inhalation. The number of explosive cough sounds occurring within the first 15 seconds after inhalation were recorded. Nonlinear mixed-effects modeling was used to estimate the Emax. Population pharmacodynamic modeling was performed in NONMEM 7.3. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.

2. Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50) [2 hours post-dose]

   The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with ATP was assessed in male and female healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 and 4. The concentration of ATP required to induce 50% of the Emax (ED50) was assessed. For ATP challenge, doubling concentrations from 0.227 μmol/mL to 929 μmol/mL were prepared by dilution of stock solutions with saline, and were administered by inhalation. Nonlinear mixed-effects modeling was used to estimate the ED50. Population pharmacodynamic modeling was performed in NONMEM 7.3 using Laplace estimation method. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.

3. Concentrations of Capsaicin Inducing 2 or More Coughs (C2) [2 hours post-dose]

   The concentrations of capsaicin inducing 2 or more coughs (C2) in participants were assessed in Periods 1 and 2. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation.

4. Concentrations of Capsaicin Inducing 5 or More Coughs (C5) [2 hours post-dose]

   The concentrations of capsaicin inducing 5 or more coughs (C5) in participants were assessed in Periods 1 and 2. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation.

5. Concentrations of ATP Inducing 2 or More Coughs (C2) [2 hours post-dose]

   The concentrations of ATP inducing 2 or more coughs (C2) in participants were assessed in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 to 929 μmol/mL were prepared from ATP powder, dissolved and diluted in saline, and administered by inhalation.

6. Concentrations of ATP Inducing 5 or More Coughs (C5) [2 hours post-dose]

   The concentrations of ATP inducing 5 or more coughs (C5) in participants were assessed in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 to 929 μmol/mL were prepared from ATP powder, dissolved and diluted in saline, and administered by inhalation.

7. Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants Only) [At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2]

   In response to capsaicin challenges in Periods 1 and 2, participants with chronic cough completed a visual analogue scale (VAS) at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS the severity of their urge to cough between 0 mm (no urge-to-cough) and 100 mm (worst urge-to-cough).

8. Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants Only) [At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2]

   In response to ATP challenges in Periods 3 and 4, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS the severity of their urge to cough between 0 mm (no urge-to-cough) and 100 mm (worst urge-to-cough).

9. Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants Only) [At the end of a 4-hour post-dose observation period; at the end of a 24-hour observation period on Day 2]

   In response to capsaicin challenges in Periods 1 and 2, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS their cough severity between 0 mm (no cough) and 100 mm (worst cough).

10. Cough Severity in Response to ATP Challenge (Chronic Cough Participants Only) [At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2]

    In response to ATP challenge in Periods 3 and 4, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS their cough severity between 0 mm (no cough) and 100 mm (worst cough).

11. Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge [From start of challenge (2 hours post-dose) to bedtime; up to 12 hours]

    Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant's clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of capsaicin challenge to bedtime on Day 1 in Periods 1 and 2. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour.

12. Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge [From start of challenge (2 hours post-dose) to bedtime; up to 12 hours]

    Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant's clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of ATP challenge to bedtime on Day 1 in Periods 3 and 4. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour.

13. Percentage of Participants Who Experienced at Least One Adverse Event [Up to Day 41]

    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

14. Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event [Up to Day 24]

    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Have provided written informed voluntary consent;

• Be able to speak, read, and understand English;

• Be males or females, of any race, between 18 and 80 years of age, inclusive;

• Have a body mass index (BMI) ≥18 and <35.0 kg/m2;

• Be in good general health with no clinically relevant abnormalities based on the medical history, physical examination, clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), and 12 lead electrocardiogram;

• Women of child bearing potential must have a negative pregnancy test at Screening and prior to randomization.

• Women of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug;

• Male subjects with partners of child-bearing potential (as defined in Inclusion No. 8) must use 2 methods of acceptable birth control, 1 of which must be a barrier method;

• Subjects with chronic cough

• Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions

Exclusion Criteria:

• Current smoker;

• Individuals who have given up smoking within the past 6 months, or those with >20 pack-year smoking history(chronic cough subjects), or >10 pack-year smoking history (healthy subjects);

• History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks prior to Screening or prior to randomization;

• History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (with the exception of < 3 excised basal cell carcinomas);

• History of a diagnosis of drug or alcohol dependency or abuse within the last 3 years;

• In the opinion of the Principal Investigator, an uncontrolled or unstable clinically significant neurological, psychiatric, respiratory, cardiovascular, peripheral vascular, gastrointestinal, hepatic, pancreatic, endocrinological, hematological, or immunological disorder or an active infection;

• Clinically significant abnormal electrocardiogram (ECG) at Screening

• Significantly abnormal laboratory tests at Screening

• Breastfeeding;

• In the judgement of the Principal Investigator, 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 and would make the subject inappropriate for entry into this trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Medicines Evaluation Unit	Manchester		United Kingdom	M23 9QZ

Sponsors and Collaborators

• Afferent Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Afferent Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02397460
• Other Study ID Numbers: 7264-015; AF-219-015; MK-7264-015; 2015-000464-34
• First Posted: Mar 25, 2015
• Last Update Posted: Feb 12, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Cough

Study Results

Participant Flow

Arm/Group Title	Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/Healthy	Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/Healthy	Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/CC	Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/CC	Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/Healthy	Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/Healthy	Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/CC	Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/CC
Arm/Group Description	Healthy participants in Cohort 1/Sequence A received single doses of placebo (PBO) on Day 1 of Periods 1 and 3 and single doses of gefapixant 300 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 1/Sequence B received single doses of gefapixant 300 mg on Day 1 of Periods 1 and 3 and singles doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough (CC) in Cohort 1/Sequence A received singles doses of placebo on Day 1 of Periods 1 and 3 and single doses of gefapixant 300 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 1/Sequence B received singles doses of gefapixant 300 mg on Day 1 of Periods 1 and 3 and single doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 2/Sequence A received singles doses of placebo on Day 1 of Periods 1 and 3 and single doses of gefapixant 50 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 2/Sequence B received single doses of gefapixant 50 mg on Day 1 of Periods 1 and 3 and single doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 2/Sequence A received singles doses of placebo on Day of Periods 1 and 3 and singles doses of gefapixant 50 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 2/Sequence B received singles doses of gefapixant 50 mg on Day 1 of Periods 1 and 3 and singles doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.
Period Title: Treatment Period 1
STARTED	7	7	6	6	6	6	6	6
COMPLETED	7	7	6	6	6	6	6	6
NOT COMPLETED	0	0	0	0	0	0	0	0
Period Title: Treatment Period 1
STARTED	7	7	6	6	6	6	6	6
COMPLETED	7	7	6	6	6	6	6	5
NOT COMPLETED	0	0	0	0	0	0	0	1
Period Title: Treatment Period 1
STARTED	7	7	6	6	6	6	6	5
COMPLETED	7	7	6	6	6	6	6	5
NOT COMPLETED	0	0	0	0	0	0	0	0
Period Title: Treatment Period 1
STARTED	7	7	6	6	6	6	6	5
COMPLETED	7	6	6	6	5	6	6	5
NOT COMPLETED	0	1	0	0	1	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/Healthy	Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/Healthy	Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/CC	Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/CC	Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/Healthy	Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/Healthy	Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/CC	Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/CC	Total
Arm/Group Description	Healthy participants in Cohort 1/Sequence A received single doses of placebo (PBO) on Day 1 of Periods 1 and 3 and single doses of gefapixant 300 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 1/Sequence B received single doses of gefapixant 300 mg on Day 1 of Periods 1 and 3 and singles doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough (CC) in Cohort 1/Sequence A received singles doses of placebo on Day 1 of Periods 1 and 3 and single doses of gefapixant 300 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 1/Sequence B received singles doses of gefapixant 300 mg on Day 1 of Periods 1 and 3 and single doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 2/Sequence A received singles doses of placebo on Day 1 of Periods 1 and 3 and single doses of gefapixant 50 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Healthy participants in Cohort 2/Sequence B received single doses of gefapixant 50 mg on Day 1 of Periods 1 and 3 and single doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 2/Sequence A received singles doses of placebo on Day of Periods 1 and 3 and singles doses of gefapixant 50 mg on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Participants with chronic cough in Cohort 2/Sequence B received singles doses of gefapixant 50 mg on Day 1 of Periods 1 and 3 and singles doses of placebo on Day 1 of Periods 2 and 4. (Each treatment period consisted of Day 1 and Day 2.) There was a minimum 48-hour washout period between treatment periods.	Total of all reporting groups
Overall Participants	7	7	6	6	6	6	6	6	50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.1 (11.87)	40.9 (6.20)	61.0 (9.25)	59.5 (8.38)	35.0 (8.17)	34.7 (7.42)	60.5 (6.83)	55 (9.01)	47.2 (14.2)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	5 83.3%	5 83.3%	0 0%	0 0%	5 83.3%	4 66.7%	19 38%
Male	7 100%	7 100%	1 16.7%	1 16.7%	6 100%	6 100%	1 16.7%	2 33.3%	31 62%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose primary endpoint assessment of Emax in response to capsaicin challenge

Arm/Group Title	Placebo/Healthy Males	Placebo/Chronic Cough Males	Placebo/Chronic Cough Females	Gefapixant 50 mg/Healthy Males	Gefapixant 50 mg/Chronic Cough Males	Gefapixant 50 mg/Chronic Cough Females	Gefapixant 300 mg/Healthy Males	Gefapixant 300 mg/Chronic Cough Males	Gefapixant 300 mg/Chronic Cough Females
Arm/Group Description	Healthy males who received single doses of placebo in Periods 1 and 2	Males with chronic cough who received single doses of placebo in Periods 1 and 2	Females with chronic cough who received single doses of placebo in Periods 1 and 2	Healthy males who received single doses of gefapixant 50 mg in Periods 1 and 2	Males with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2	Females with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2	Healthy males who received single doses of gefapixant 300 mg in Periods 1 and 2	Males with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2	Females with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2
Measure Participants	26	5	18	26	5	18	26	5	18
Number [Emax (Explosive coughs/15 sec)]	4.14	4.14	7.57	3.66	3.37	6.17	3.66	3.37	6.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Healthy Males, Placebo/Chronic Cough Males, Placebo/Chronic Cough Females, Gefapixant 50 mg/Healthy Males, Gefapixant 50 mg/Chronic Cough Males, Gefapixant 50 mg/Chronic Cough Females, Gefapixant 300 mg/Healthy Males, Gefapixant 300 mg/Chronic Cough Males, Gefapixant 300 mg/Chronic Cough Females
	Comments	Treatment effects on Emax following capsaicin challenge were modeled for dose dependence and were estimated on the basis of disease status for participants who were healthy or had chronic cough and received gefapixant 50 mg, gefapixant 300 mg, or placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose primary endpoint assessment of ED50 in response to capsaicin challenge

Arm/Group Title	Placebo/Healthy Males	Placebo/Chronic Cough Males	Placebo/Chronic Cough Females	Gefapixant 50 mg/Healthy Males	Gefapixant 50 mg/Chronic Cough Males	Gefapixant 50 mg/Chronic Cough Females	Gefapixant 300 mg/Healthy Males	Gefapixant 300 mg/Chronic Cough Males	Gefapixant 300 mg/Chronic Cough Females
Arm/Group Description	Healthy males who received single doses of placebo in Periods 1 and 2	Males with chronic cough who received single doses of placebo in Periods 1 and 2	Females with chronic cough who received single doses of placebo in Periods 1 and 2	Healthy males who received single doses of gefapixant 50 mg in Periods 1 and 2	Males with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2	Females with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2	Healthy males who received single doses of gefapixant 300 mg in Periods 1 and 2	Males with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2	Females with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2
Measure Participants	26	5	18	26	5	18	26	5	18
Number [µM]	33	33	9.56	33	33	9.56	33	33	9.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo/Healthy Males, Placebo/Chronic Cough Males, Placebo/Chronic Cough Females, Gefapixant 50 mg/Healthy Males, Gefapixant 50 mg/Chronic Cough Males, Gefapixant 50 mg/Chronic Cough Females, Gefapixant 300 mg/Healthy Males, Gefapixant 300 mg/Chronic Cough Males, Gefapixant 300 mg/Chronic Cough Females
	Comments	Treatment effects following capsaicin challenge were modeled for dose. dependence and were estimated on the basis of disease status for participants who had chronic cough and received gefapixant 50 mg, gefapixant 300 mg, or placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax)
Description	The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with adenosine triphosphate (ATP) was assessed in male and female healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 μmol/mL to 929 μmol/mL were prepared from ATP powder dissolved in saline, and were administered by inhalation. The number of explosive cough sounds occurring within the first 15 seconds after inhalation were recorded. Nonlinear mixed-effects modeling was used to estimate the Emax. Population pharmacodynamic modeling was performed in NONMEM 7.3. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of Emax in response to ATP challenge

Arm/Group Title	Placebo/Healthy Males	Placebo/Chronic Cough Males	Placebo/Chronic Cough Females	Gefapixant 50 mg/Healthy Males	Gefapixant 50 mg/Chronic Cough Males	Gefapixant 50 mg/Chronic Cough Females	Gefapixant 300 mg/Healthy Males	Gefapixant 300 mg/Chronic Cough Males	Gefapixant 300 mg/Chronic Cough Females
Arm/Group Description	Healthy males who received single doses of placebo in Periods 3 and 4	Chronic cough males who received single doses of placebo in Periods 3 and 4	Females with chronic cough who received single doses of placebo in Periods 3 and 4	Healthy males who received single doses of gefapixant 50 mg in Periods 3 and 4	Males with chronic cough who received single doses of gefapixant 50 mg in Periods 3 and 4	Females with chronic cough who received single doses of gefapixant 50 mg in Periods 3 and 4	Healthy males who received single doses of gefapixant 300 mg in Periods 3 and 4	Males with chronic cough who received single doses of gefapixant 300 mg in Periods 3 and 4	Females with chronic cough who received single doses of gefapixant 300 mg in Periods 3 and 4
Measure Participants	26	4	18	26	4	18	26	4	18
Number [Emax (Explosive coughs/15 sec)]	2.35	2.35	5.4	2.35	2.35	5.4	2.35	2.35	5.4

4. Secondary Outcome

Title	Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)
Description	The effect of single doses of 50 mg and 300 mg gefapixant on cough reflex sensitivity to challenge with ATP was assessed in male and female healthy participants and participants with chronic cough. ATP-evoked cough challenge was performed 2 hours post-dose in Periods 3 and 4. The concentration of ATP required to induce 50% of the Emax (ED50) was assessed. For ATP challenge, doubling concentrations from 0.227 μmol/mL to 929 μmol/mL were prepared by dilution of stock solutions with saline, and were administered by inhalation. Nonlinear mixed-effects modeling was used to estimate the ED50. Population pharmacodynamic modeling was performed in NONMEM 7.3 using Laplace estimation method. Data exploration, goodness-of-fit plots, statistical analyses, and simulations were performed in Matlab R2015a. Note: All values presented in this table are model-based.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of ED50 in response to ATP challenge

Arm/Group Title	Placebo/Healthy Males	Placebo/Chronic Cough Males	Placebo/Chronic Cough Females	Gefapixant 50 mg/Healthy Males	Gefapixant 50 mg/Chronic Cough Males	Gefapixant 50 mg/Chronic Cough Females	Gefapixant 300 mg/Healthy Males	Gefapixant 300 mg/Chronic Cough Males	Gefapixant 300 mg/Chronic Cough Females
Arm/Group Description	Healthy males who received single doses of placebo in Periods 3 and 4	Chronic cough males who received single doses of placebo in Periods 3 and 4	Females with chronic cough who received single doses of placebo in Periods 3 and 4	Healthy males who received single doses of gefapixant 50 mg in Periods 3 and 4	Males with chronic cough who received single doses of gefapixant 50 mg in Periods 3 and 4	Females with chronic cough who received single doses of gefapixant 50 mg in Periods 3 and 4	Healthy males who received single doses of gefapixant 300 mg in Periods 3 and 4	Males with chronic cough who received single doses of gefapixant 300 mg in Periods 3 and 4	Females with chronic cough who received single doses of gefapixant 300 mg in Periods 3 and 4
Measure Participants	14	4	18	26	4	18	26	4	18
Number [µmol/mL]	54.9	54.9	8.63	119.13	155.92	24.51	119.13	192.7	30.29

5. Secondary Outcome

Title	Concentrations of Capsaicin Inducing 2 or More Coughs (C2)
Description	The concentrations of capsaicin inducing 2 or more coughs (C2) in participants were assessed in Periods 1 and 2. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of C2 in response to capsaicin challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy males and females in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Healthy males and females in Cohort 1 who received single doses of placebo in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Males and females in Cohort 1 with chronic cough who received single doses of placebo in Periods 1 and 2 combined	Healthy males and females who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Healthy males and females in Cohort 2 who received single doses of placebo in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 2 who received single doses of placebo in Periods 1 and 2 combined
Measure Participants	12	14	10	10	12	12	10	12
Median (Full Range) [µM]	31.25	31.25	3.90	7.81	15.62	23.44	15.62	5.86

6. Secondary Outcome

Title	Concentrations of Capsaicin Inducing 5 or More Coughs (C5)
Description	The concentrations of capsaicin inducing 5 or more coughs (C5) in participants were assessed in Periods 1 and 2. For capsaicin challenge, doubling concentrations from 0.49 μM to 1000 μM were prepared by dilution of stock solutions with saline, and were administered by inhalation.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of C5 in response to capsaicin challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy males and females in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Healthy males and females in Cohort 1 who received single doses of placebo in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 1 who received single doses of placebo in Periods 1 and 2 combined	Healthy males and females in Cohort 2 who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Healthy males and females in Cohort 2 who received single doses of placebo in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Males and females with chronic cough in Cohort 2 who received single doses of placebo in Periods 1 and 2 combined
Measure Participants	5	6	10	10	6	7	7	10
Median (Full Range) [µM]	31.25	62.50	3.90	11.72	250.00	125.00	15.62	5.86

7. Secondary Outcome

Title	Concentrations of ATP Inducing 2 or More Coughs (C2)
Description	The concentrations of ATP inducing 2 or more coughs (C2) in participants were assessed in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 to 929 μmol/mL were prepared from ATP powder, dissolved and diluted in saline, and administered by inhalation.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of C2 in response to ATP challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy males and females in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Healthy males and females in Cohort 1 who received single doses of placebo in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 1 who received single doses of placebo in Periods 3 and 4 combined	Healthy males and females in Cohort 2 who received single doses of gefapixant 50 mg in Periods 3 and 4 combined	Healthy males and females in Cohort 2 who received single doses of placebo in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 2 who received single doses of placebo in Periods 3 and 4 combined
Measure Participants	10	11	7	11	9	8	8	9
Median (Full Range) [mg/mL]	192.00	64.00	8.00	1.00	16.00	24.00	4.25	4.00

8. Secondary Outcome

Title	Concentrations of ATP Inducing 5 or More Coughs (C5)
Description	The concentrations of ATP inducing 5 or more coughs (C5) in participants were assessed in Periods 3 and 4. For ATP challenge, doubling concentrations from 0.227 to 929 μmol/mL were prepared from ATP powder, dissolved and diluted in saline, and administered by inhalation.
Time Frame	2 hours post-dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of C5 in response to ATP challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Chronic Cough/Gefapixant 300 mg	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy males and females in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Healthy males and females in Cohort 1 who received single doses of placebo in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 1 who received single doses of placebo in Periods 3 and 4 combined	Healthy males and females in Cohort 2 who received single doses of gefapixant 50 mg in Periods 3 and 4 combined	Healthy males and females in Cohort 2 who received single doses of placebo in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 3 and 4 combined	Males and females with chronic cough in Cohort 2 who received placebo in Periods 3 and 4 combined
Measure Participants	2	5	7	8	4	4	5	8
Median (Full Range) [mg/mL]	192.00	128.00	8.00	16.50	64.00	32.00	128.00	4.00

9. Secondary Outcome

Title	Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants Only)
Description	In response to capsaicin challenges in Periods 1 and 2, participants with chronic cough completed a visual analogue scale (VAS) at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS the severity of their urge to cough between 0 mm (no urge-to-cough) and 100 mm (worst urge-to-cough).
Time Frame	At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2

Outcome Measure Data

Analysis Population Description

All randomized participants with chronic cough who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of urge-to-cough in response to capsaicin challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 1 who received single doses of placebo in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received single doses of placebo in Periods 1 and 2 combined
Measure Participants	12	12	12	11
Day 1	28.9 (29.79)	38.6 (26.82)	36.6 (30.84)	20.5 (11.54)
Day 2	28.2 (32.72)	46.7 (29.20)	41.8 (31.02)	36.7 (23.28)

10. Secondary Outcome

Title	Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants Only)
Description	In response to ATP challenges in Periods 3 and 4, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS the severity of their urge to cough between 0 mm (no urge-to-cough) and 100 mm (worst urge-to-cough).
Time Frame	At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2

Outcome Measure Data

Analysis Population Description

All randomized participants with chronic cough who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of urge-to-cough in response to ATP challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 1 who received single doses of placebo in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received single doses of placebo in Periods 3 and 4 combined
Measure Participants	12	12	11	11
Day 1	19.8 (23.54)	34.4 (26.78)	21.5 (22.45)	25.3 (19.69)
Day 2	21.6 (20.65)	39.8 (26.51)	27.5 (29.54)	37.5 (27.33)

11. Secondary Outcome

Title	Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants Only)
Description	In response to capsaicin challenges in Periods 1 and 2, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS their cough severity between 0 mm (no cough) and 100 mm (worst cough).
Time Frame	At the end of a 4-hour post-dose observation period; at the end of a 24-hour observation period on Day 2

Outcome Measure Data

Analysis Population Description

All randomized participants with chronic cough who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of cough severity in response to capsaicin challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received gefapixant 300 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 1 who received placebo in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received gefapixant 50 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received placebo in Periods 1 and 2 combined.
Measure Participants	12	12	12	11
Day 1	28.2 (30.71)	35.7 (24.32)	30.9 (27.22)	20.5 (12.75)
Day 2	25.8 (30.20)	44.3 (27.43)	39.8 (28.97)	35.5 (22.25)

12. Secondary Outcome

Title	Cough Severity in Response to ATP Challenge (Chronic Cough Participants Only)
Description	In response to ATP challenge in Periods 3 and 4, participants with chronic cough completed a VAS at the end of a 4-hour post-dose observation period on Day 1; and at end of 24-hour observation period on Day 2. For both periods, participants were asked to mark on a 100 mm VAS their cough severity between 0 mm (no cough) and 100 mm (worst cough).
Time Frame	At the end of a 4-hour post-dose observation period on Day 1; at the end of a 24-hour observation period on Day 2

Outcome Measure Data

Analysis Population Description

All randomized participants with chronic cough who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of cough severity in response to ATP challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 1 who received placebo in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received gefapixant 50 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received placebo in Periods 3 and 4 combined
Measure Participants	12	12	11	11
Day 1	21.5 (27.06)	32.7 (24.23)	21.2 (21.04)	23.5 (16.02)
Day 2	18.9 (18.29)	36.8 (26.50)	27.5 (26.78)	35.5 (24.07)

13. Secondary Outcome

Title	Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge
Description	Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant's clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of capsaicin challenge to bedtime on Day 1 in Periods 1 and 2. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour.
Time Frame	From start of challenge (2 hours post-dose) to bedtime; up to 12 hours

Outcome Measure Data

Analysis Population Description

All randomized participants with chronic cough who received at least 1 dose of study medication and had at least 1 post-dose secondary endpoint assessment of daytime cough frequency in response to capsaicin challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 1 who received single doses of placebo in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg in Periods 1 and 2 combined	Participants with chronic cough in Cohort 2 who received single doses of placebo in treatment Periods 1 and 2 combined
Measure Participants	12	12	12	12
Mean (Standard Deviation) [coughs/hour]	13.7 (13.85)	19.1 (16.76)	15.5 (16.92)	20.3 (13.27)

14. Secondary Outcome

Title	Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge
Description	Daily cough frequency monitoring was performed in participants with chronic cough, who were attached to a digital sound recorder with 2 microphones (a lapel air microphone attached to the participant's clothing and an adhesive chest wall microphone attached to the skin at the top of the sternum). Participants wore the sound recorder from the start of ATP challenge to bedtime on Day 1 in Periods 3 and 4. The resulting recording was processed by software which cut out the majority of speech and background noise but retained cough sounds. The investigator listened to the recording and documented the number of coughs per hour.
Time Frame	From start of challenge (2 hours post-dose) to bedtime; up to 12 hours

Outcome Measure Data

Analysis Population Description

All treated participants with chronic cough who had at least 1 post-dose secondary endpoint assessment of daytime cough frequency in response to ATP challenge

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 1 who received placebo in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received gefapixant 50 mg in Periods 3 and 4 combined	Participants with chronic cough in Cohort 2 who received placebo in Periods 3 and 4 combined
Measure Participants	12	12	11	11
Mean (Standard Deviation) [coughs/hour]	10.3 (11.65)	22.3 (15.48)	15.6 (17.31)	26.4 (16.75)

15. Secondary Outcome

Title	Percentage of Participants Who Experienced at Least One Adverse Event
Description	An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time Frame	Up to Day 41

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy participants in Cohort 1 who received singles doses of gefapixant 300 mg	Healthy participants in Cohort 1 who received single doses of placebo	Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg	Participants with chronic cough in Cohort 1 who received single doses of placebo	Healthy participants in Cohort 2 who received single doses of gefapixant 50 mg	Healthy participants in Cohort 2 who received single doses of placebo	Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg	Participants with chronic cough in Cohort 2 who received single doses of placebo
Measure Participants	14	14	12	12	12	12	12	11
Number [Percentage of participants]	100.0 1428.6%	35.7 510%	100.0 1666.7%	58.3 971.7%	75.0 1250%	33.3 555%	50.0 833.3%	27.3 455%

16. Secondary Outcome

Title	Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
Description	An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time Frame	Up to Day 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study medication

Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy	Cohort 1: Placebo/Healthy	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Healthy	Cohort 2: Placebo/Healthy	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy participants in Cohort 1 who received single doses of gefapixant 300 mg	Healthy participants in Cohort 1 who received single doses of placebo	Participants with chronic cough in Cohort 1 who received singles doses of gefapixant 300 mg	Participants with chronic cough in Cohort 1 who received single doses of placebo	Healthy participants in Cohort 2 who received single doses of gefapixant 50 mg	Healthy participants in Cohort 2 who received single doses of placebo	Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg	Participants with chronic cough in Cohort 2 who received single doses of placebo
Measure Participants	14	14	12	12	12	12	12	11
Number [Percentage of participants]	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%	0.0 0%

Adverse Events

Time Frame	Up to Day 41
Adverse Event Reporting Description	All randomized participants who received at least 1 dose of study medication.
Arm/Group Title	Cohort 1: Gefapixant 300 mg/Healthy		Cohort 1: Placebo/Healthy		Cohort 1: Gefapixant 300 mg/Chronic Cough		Cohort 1: Placebo/Chronic Cough		Cohort 2: Gefapixant 50 mg/Healthy		Cohort 2: Placebo/Healthy		Cohort 2: Gefapixant 50 mg/Chronic Cough		Cohort 2: Placebo/Chronic Cough
Arm/Group Description	Healthy participants in Cohort 1 who received single doses of gefapixant 300 mg		Healthy participants in Cohort 1 who received single doses of placebo		Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg		Participants with chronic cough in Cohort 1 who received single doses of placebo		Healthy participants in Cohort 2 who received single doses of gefapixant 50 mg		Healthy participants in Cohort 2 who received single doses of placebo		Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg		Participants with chronic cough in Cohort 2 who received single doses of placebo
All Cause Mortality
	Cohort 1: Gefapixant 300 mg/Healthy		Cohort 1: Placebo/Healthy		Cohort 1: Gefapixant 300 mg/Chronic Cough		Cohort 1: Placebo/Chronic Cough		Cohort 2: Gefapixant 50 mg/Healthy		Cohort 2: Placebo/Healthy		Cohort 2: Gefapixant 50 mg/Chronic Cough		Cohort 2: Placebo/Chronic Cough
	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	0/14 (0%)		0/14 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/11 (0%)
Serious Adverse Events
	Cohort 1: Gefapixant 300 mg/Healthy		Cohort 1: Placebo/Healthy		Cohort 1: Gefapixant 300 mg/Chronic Cough		Cohort 1: Placebo/Chronic Cough		Cohort 2: Gefapixant 50 mg/Healthy		Cohort 2: Placebo/Healthy		Cohort 2: Gefapixant 50 mg/Chronic Cough		Cohort 2: Placebo/Chronic Cough
	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	0/14 (0%)		0/14 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Gefapixant 300 mg/Healthy		Cohort 1: Placebo/Healthy		Cohort 1: Gefapixant 300 mg/Chronic Cough		Cohort 1: Placebo/Chronic Cough		Cohort 2: Gefapixant 50 mg/Healthy		Cohort 2: Placebo/Healthy		Cohort 2: Gefapixant 50 mg/Chronic Cough		Cohort 2: Placebo/Chronic Cough
	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	14/14 (100%)		5/14 (35.7%)		12/12 (100%)		7/12 (58.3%)		9/12 (75%)		4/12 (33.3%)		6/12 (50%)		3/11 (27.3%)
Ear and labyrinth disorders
Ear pain	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	2
Dry mouth	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Dyspepsia	1/14 (7.1%)	1	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Hypoaesthesia oral	1/14 (7.1%)	1	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Nausea	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1
Paraesthesia oral	4/14 (28.6%)	4	0/14 (0%)	0	4/12 (33.3%)	4	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0
Reflux gastritis	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Salivary hypersecretion	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Tongue coated	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Tooth deposit	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Vomiting	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
General disorders
Chest discomfort	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/11 (0%)	0
Fatigue	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Pain	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Infections and infestations
Gastroenteritis	1/14 (7.1%)	1	1/14 (7.1%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Oral herpes	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Rhinitis	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Upper respiratory tract infection	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Excoriation	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Musculoskeletal pain	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1
Spinal osteoarthritis	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1
Nervous system disorders
Ageusia	0/14 (0%)	0	0/14 (0%)	0	3/12 (25%)	4	0/12 (0%)	0	4/12 (33.3%)	4	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Dizziness	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Dysgeusia	13/14 (92.9%)	20	1/14 (7.1%)	1	9/12 (75%)	15	1/12 (8.3%)	1	4/12 (33.3%)	5	0/12 (0%)	0	3/12 (25%)	5	1/11 (9.1%)	1
Headache	3/14 (21.4%)	3	2/14 (14.3%)	2	5/12 (41.7%)	5	2/12 (16.7%)	2	2/12 (16.7%)	2	1/12 (8.3%)	1	1/12 (8.3%)	1	2/11 (18.2%)	2
Hypogeusia	2/14 (14.3%)	2	0/14 (0%)	0	3/12 (25%)	3	0/12 (0%)	0	2/12 (16.7%)	2	0/12 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0
VIIth Nerve Paralysis	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Psychiatric disorders
Anxiety	1/14 (7.1%)	1	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/14 (0%)	0	1/14 (7.1%)	1	0/12 (0%)	0	0/12 (0%)	0	2/12 (16.7%)	2	3/12 (25%)	3	3/12 (25%)	3	0/11 (0%)	0
Dry throat	1/14 (7.1%)	1	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1
Oropharyngeal discomfort	0/14 (0%)	0	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Oropharyngeal pain	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	1/12 (8.3%)	1	0/12 (0%)	0	0/11 (0%)	0
Pharyngeal hypoaesthesia	2/14 (14.3%)	2	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Throat irritation	0/14 (0%)	0	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Wheezing	0/14 (0%)	0	1/14 (7.1%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/11 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	1/14 (7.1%)	1	0/14 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/11 (0%)	0
Vascular disorders
Hot flush	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	1/12 (8.3%)	1	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1
Hypertension	0/14 (0%)	0	0/14 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1

Limitations/Caveats

[Not Specified]

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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. These obligations of confidentiality and non-use shall in no way diminish such obligations as set forth in the Confidentiality Agreement between the Sponsor and the Investigator(s).