CompletedNCT02397460Updated Feb 12, 2021Results posted

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

A Phase 2 interventional study of Gefapixant and Placebo in Refractory Chronic Cough, sponsored by Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA). Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-02-12.

Sponsored by Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 50
Allocation: Randomized
Ages: 18 Years to 80 Years
Sex: All

Study 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.

Read the 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).

Conditions studied

Refractory Chronic Cough

Browse trials for

In context

Cough

346 studies on the registry are indexed under Cough; 71 are open to participants now.

This study's enrollment of 50 is below the median of 70 across 263 interventional studies indexed under Cough.

Browse Cough studies →

Lead sponsor

Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) is the lead sponsor of 15 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 80 Years
Sexes eligible: 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

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 50 participants (actual)

Study arms

Experimental
Gefapixant 50 mg
Gefapixant 50 mg (1 tablet) administered as a single dose
Drug: Gefapixant
Experimental
Gefapixant 300 mg
Gefapixant 300 mg (6 tablets) administered as a single dose
Drug: Gefapixant
Placebo comparator
Placebo
Placebo-matching tablets administered as a single dose
Drug: Placebo

Interventions

DrugGefapixant
Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets)
Also known as: AF-219, MK-7264
DrugPlacebo

What researchers measure

Primary outcomes

Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax)
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
Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)
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

Secondary outcomes

Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax)
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
Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)
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
Concentrations of Capsaicin Inducing 2 or More Coughs (C2)
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
Concentrations of Capsaicin Inducing 5 or More Coughs (C5)
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
Concentrations of ATP Inducing 2 or More Coughs (C2)
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
Concentrations of ATP Inducing 5 or More Coughs (C5)
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
Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants Only)
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
Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants Only)
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
Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants Only)
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
Cough Severity in Response to ATP Challenge (Chronic Cough Participants Only)
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
Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge
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
Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge
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
Percentage of Participants Who Experienced at Least One Adverse Event
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
Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
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

Results

Posted Feb 12, 2021

Participant flow

Treatment Period 1

Participant flow — Treatment Period 1
Milestone	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
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

Treatment Period 2

Participant flow — Treatment Period 2
Milestone	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
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
Withdrew: Adverse event	0	0	0	0	0	0	0	1

Treatment Period 3

Participant flow — Treatment Period 3
Milestone	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
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

Treatment Period 4

Participant flow — Treatment Period 4
Milestone	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
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
Withdrew: Adverse event	0	1	0	0	0	0	0	0
Withdrew: Physician decision	0	0	0	0	1	0	0	0

Outcome measures

PrimaryCough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax)

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
Reported as:: Number · Emax (Explosive coughs/15 sec)

Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax)
Emax (Explosive coughs/15 sec)	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
Cough Reflex Sensitivity to Capsaicin Measured by Maximal Cough Response (Emax)	4.14	4.14	7.57	3.66	3.37	6.17	3.66	3.37	6.17

Statistical analysis

Placebo/Healthy Males vs Placebo/Chronic Cough Males vs Placebo/Chronic Cough Females vs Gefapixant 50 mg/Healthy Males vs Gefapixant 50 mg/Chronic Cough Males vs Gefapixant 50 mg/Chronic Cough Females vs Gefapixant 300 mg/Healthy Males vs Gefapixant 300 mg/Chronic Cough Males vs Gefapixant 300 mg/Chronic Cough Females · Mixed Models Analysis · p = < 0.0001

PrimaryCough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)

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
Reported as:: Number · µM

Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)
µM	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
Cough Reflex Sensitivity to Capsaicin Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)	33	33	9.56	33	33	9.56	33	33	9.56

Statistical analysis

Placebo/Healthy Males vs Placebo/Chronic Cough Males vs Placebo/Chronic Cough Females vs Gefapixant 50 mg/Healthy Males vs Gefapixant 50 mg/Chronic Cough Males vs Gefapixant 50 mg/Chronic Cough Females vs Gefapixant 300 mg/Healthy Males vs Gefapixant 300 mg/Chronic Cough Males vs Gefapixant 300 mg/Chronic Cough Females · Mixed Models Analysis · p = < 0.0001

SecondaryCough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax)

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
Reported as:: Number · Emax (Explosive coughs/15 sec)

Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax)
Emax (Explosive coughs/15 sec)	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
Cough Reflex Sensitivity to Adenosine Triphosphate (ATP) Measured by Maximal Cough Response (Emax)	2.35	2.35	5.4	2.35	2.35	5.4	2.35	2.35	5.4

SecondaryCough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)

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
Reported as:: Number · µmol/mL

Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)
µmol/mL	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
Cough Reflex Sensitivity to ATP Measured by the Tussive Concentration Required to Achieve 50% of Emax (ED50)	54.9	54.9	8.63	119.13	155.92	24.51	119.13	192.7	30.29

SecondaryConcentrations of Capsaicin Inducing 2 or More Coughs (C2)

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
Reported as:: Median · µM

Concentrations of Capsaicin Inducing 2 or More Coughs (C2)
µM	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
Concentrations of Capsaicin Inducing 2 or More Coughs (C2)	31.25 (4 to 1000)	31.25 (4 to 500)	3.90 (0 to 16)	7.81 (0 to 31)	15.62 (2 to 63)	23.44 (8 to 125)	15.62 (0 to 125)	5.86 (0 to 250)

SecondaryConcentrations of Capsaicin Inducing 5 or More Coughs (C5)

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
Reported as:: Median · µM

Concentrations of Capsaicin Inducing 5 or More Coughs (C5)
µM	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
Concentrations of Capsaicin Inducing 5 or More Coughs (C5)	31.25 (16 to 250)	62.50 (16 to 1000)	3.90 (0 to 31)	11.72 (0 to 125)	250.00 (63 to 500)	125.00 (63 to 500)	15.62 (2 to 63)	5.86 (0 to 31)

SecondaryConcentrations of ATP Inducing 2 or More Coughs (C2)

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
Reported as:: Median · mg/mL

Concentrations of ATP Inducing 2 or More Coughs (C2)
mg/mL	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
Concentrations of ATP Inducing 2 or More Coughs (C2)	192.00 (8 to 256)	64.00 (1 to 512)	8.00 (0 to 64)	1.00 (0 to 64)	16.00 (8 to 256)	24.00 (2 to 512)	4.25 (0 to 512)	4.00 (0 to 256)

SecondaryConcentrations of ATP Inducing 5 or More Coughs (C5)

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
Reported as:: Median · mg/mL

Concentrations of ATP Inducing 5 or More Coughs (C5)
mg/mL	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
Concentrations of ATP Inducing 5 or More Coughs (C5)	192.00 (128 to 256)	128.00 (64 to 256)	8.00 (0 to 64)	16.50 (0 to 512)	64.00 (32 to 256)	32.00 (2 to 32)	128.00 (8 to 512)	4.00 (0 to 128)

SecondaryUrge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants Only)

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
Reported as:: Mean · Score on a scale

Urge-to-Cough in Response to Capsaicin Challenge (Chronic Cough Participants Only)
Score on a scale	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
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

SecondaryUrge-to-Cough in Response to ATP Challenge (Chronic Cough Participants Only)

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
Reported as:: Mean · Score on a scale

Urge-to-Cough in Response to ATP Challenge (Chronic Cough Participants Only)
Score on a scale	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
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

SecondaryCough Severity in Response to Capsaicin Challenge (Chronic Cough Participants Only)

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
Reported as:: Mean · Score on a scale

Cough Severity in Response to Capsaicin Challenge (Chronic Cough Participants Only)
Score on a scale	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
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

SecondaryCough Severity in Response to ATP Challenge (Chronic Cough Participants Only)

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
Reported as:: Mean · Score on a scale

Cough Severity in Response to ATP Challenge (Chronic Cough Participants Only)
Score on a scale	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
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

SecondaryDaytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge

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
Reported as:: Mean · coughs/hour

Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge
coughs/hour	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Daytime Cough Frequency in Participants With Chronic Cough Who Underwent Capsaicin Challenge	13.7 ± 13.85	19.1 ± 16.76	15.5 ± 16.92	20.3 ± 13.27

SecondaryDaytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge

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
Reported as:: Mean · coughs/hour

Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge
coughs/hour	Cohort 1: Gefapixant 300 mg/Chronic Cough	Cohort 1: Placebo/Chronic Cough	Cohort 2: Gefapixant 50 mg/Chronic Cough	Cohort 2: Placebo/Chronic Cough
Daytime Cough Frequency in Participants With Chronic Cough Who Underwent ATP Challenge	10.3 ± 11.65	22.3 ± 15.48	15.6 ± 17.31	26.4 ± 16.75

SecondaryPercentage of Participants Who Experienced at Least One Adverse Event

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
Reported as:: Number · Percentage of participants

Percentage of Participants Who Experienced at Least One Adverse Event
Percentage of participants	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
Percentage of Participants Who Experienced at Least One Adverse Event	100.0	35.7	100.0	58.3	75.0	33.3	50.0	27.3

SecondaryPercentage of Participants Who Discontinued Study Treatment Due to an Adverse Event

Time frame:: Up to Day 24
Reported as:: Number · Percentage of participants

Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event
Percentage of participants	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
Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0

Adverse events

Collected over Up to Day 41. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Cohort 1: Gefapixant 300 mg/Healthy	0/14 (0%)	0/14 (0%)	14/14 (100%)
Cohort 1: Placebo/Healthy	0/14 (0%)	0/14 (0%)	5/14 (35.7%)
Cohort 1: Gefapixant 300 mg/Chronic Cough	0/12 (0%)	0/12 (0%)	12/12 (100%)
Cohort 1: Placebo/Chronic Cough	0/12 (0%)	0/12 (0%)	7/12 (58.3%)
Cohort 2: Gefapixant 50 mg/Healthy	0/12 (0%)	0/12 (0%)	9/12 (75%)
Cohort 2: Placebo/Healthy	0/12 (0%)	0/12 (0%)	4/12 (33.3%)
Cohort 2: Gefapixant 50 mg/Chronic Cough	0/12 (0%)	0/12 (0%)	6/12 (50%)
Cohort 2: Placebo/Chronic Cough	0/11 (0%)	0/11 (0%)	3/11 (27.3%)

Most frequent other events

Showing 10 of 41

Most frequent other events
Event	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
DysgeusiaNervous system disorders	13/14	1/14	9/12	1/12	4/12	0/12	3/12	1/11
HeadacheNervous system disorders	3/14	2/14	5/12	2/12	2/12	1/12	1/12	2/11
Paraesthesia oralGastrointestinal disorders	4/14	0/14	4/12	1/12	0/12	0/12	1/12	0/11
AgeusiaNervous system disorders	0/14	0/14	3/12	0/12	4/12	0/12	0/12	0/11
HypogeusiaNervous system disorders	2/14	0/14	3/12	0/12	2/12	0/12	1/12	0/11
CoughRespiratory, thoracic and mediastinal disorders	0/14	1/14	0/12	0/12	2/12	3/12	3/12	0/11
Pharyngeal hypoaesthesiaRespiratory, thoracic and mediastinal disorders	2/14	0/14	1/12	0/12	1/12	0/12	0/12	0/11
DiarrhoeaGastrointestinal disorders	0/14	0/14	0/12	0/12	0/12	0/12	0/12	1/11
NauseaGastrointestinal disorders	1/14	0/14	0/12	0/12	0/12	0/12	0/12	1/11
Musculoskeletal painMusculoskeletal and connective tissue disorders	0/14	0/14	0/12	0/12	0/12	0/12	0/12	1/11

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	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
Mean	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
Sex: Female, Male(Participants)	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
Female	0	0	5	5	0	0	5	4	19
Male	7	7	1	1	6	6	1	2	31

Study locations

1 site

The Medicines Evaluation Unit
Manchester, M23 9QZ, United Kingdom

References and documents

Individual participant data

Plan to share: Yes — https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

No publications or documents are linked to this record.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Feb 12, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02397460
Lead sponsor: Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Responsible party: Sponsor
First posted: Mar 25, 2015
Start date: Apr 29, 2015
Primary completion: Apr 22, 2016
Completion: May 16, 2016
Results posted: Feb 12, 2021
Last update: Feb 12, 2021

Study contacts

Medical Director

study director · Merck Sharp & Dohme LLC

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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