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| ID | Type | Description | Link |
|---|---|---|---|
| AF-219-015 | Other Identifier | Afferent Protocol Number | |
| MK-7264-015 | Other Identifier | Merck Protocol Number | |
| 2015-000464-34 | EudraCT Number |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Gefapixant 50 mg | Experimental | Gefapixant 50 mg (1 tablet) administered as a single dose |
|
| Gefapixant 300 mg | Experimental | Gefapixant 300 mg (6 tablets) administered as a single dose |
|
| Placebo | Placebo Comparator | Placebo-matching tablets administered as a single dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gefapixant | Drug | Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets) |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 2 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Medicines Evaluation Unit | Manchester | M23 9QZ | United Kingdom |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/Healthy | 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. |
| FG001 | Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/Healthy | 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. |
| FG002 | Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/CC | 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. |
| FG003 | Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/CC | 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. |
| FG004 | Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/Healthy | 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. |
| FG005 | Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/Healthy | 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. |
| FG006 | Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/CC | 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. |
| FG007 | Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/CC | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 |
| |||||||||||||
| Treatment Period 2 |
| |||||||||||||
| Treatment Period 3 |
| |||||||||||||
| Treatment Period 4 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/Healthy | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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 | Posted | Number | Emax (Explosive coughs/15 sec) | 2 hours post-dose |
Up to Day 41
All randomized participants who received at least 1 dose of study medication.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1: Gefapixant 300 mg/Healthy | Healthy participants in Cohort 1 who received single doses of gefapixant 300 mg |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear pain | Ear and labyrinth disorders | MedDRA 17.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
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| ID | Term |
|---|---|
| D000096822 | Chronic Cough |
| ID | Term |
|---|---|
| D003371 | Cough |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D012818 | Signs and Symptoms, Respiratory |
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| ID | Term |
|---|---|
| C000597312 | Gefapixant |
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|
| Placebo | Drug |
|
| 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. | 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. | 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. | 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. | 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. | 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). | 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). | 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). | 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). | 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. | 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. | 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. | 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. | Up to Day 24 |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| BG001 |
| Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/Healthy |
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. |
| BG002 | Cohort 1: PBO→Gefapixant 300 mg→PBO→Gefapixant 300 mg/CC | 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. |
| BG003 | Cohort 1: Gefapixant 300 mg→PBO→Gefapixant 300 mg→PBO/CC | 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. |
| BG004 | Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/Healthy | 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. |
| BG005 | Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/Healthy | 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. |
| BG006 | Cohort 2: PBO→Gefapixant 50 mg→PBO→Gefapixant 50 mg/CC | 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. |
| BG007 | Cohort 2: Gefapixant 50 mg→PBO→Gefapixant 50 mg→PBO/CC | 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. |
| BG008 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Placebo/Healthy Males | Healthy males who received single doses of placebo in Periods 1 and 2 |
| OG001 | Placebo/Chronic Cough Males | Males with chronic cough who received single doses of placebo in Periods 1 and 2 |
| OG002 | Placebo/Chronic Cough Females | Females with chronic cough who received single doses of placebo in Periods 1 and 2 |
| OG003 | Gefapixant 50 mg/Healthy Males | Healthy males who received single doses of gefapixant 50 mg in Periods 1 and 2 |
| OG004 | Gefapixant 50 mg/Chronic Cough Males | Males with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2 |
| OG005 | Gefapixant 50 mg/Chronic Cough Females | Females with chronic cough who received single doses of gefapixant 50 mg in Periods 1 and 2 |
| OG006 | Gefapixant 300 mg/Healthy Males | Healthy males who received single doses of gefapixant 300 mg in Periods 1 and 2 |
| OG007 | Gefapixant 300 mg/Chronic Cough Males | Males with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2 |
| OG008 | Gefapixant 300 mg/Chronic Cough Females | Females with chronic cough who received single doses of gefapixant 300 mg in Periods 1 and 2 |
|
|
|
| Primary | 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. | 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 | Posted | Number | µM | 2 hours post-dose |
|
|
|
|
| Secondary | 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. | 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 | Posted | Number | Emax (Explosive coughs/15 sec) | 2 hours post-dose |
|
|
|
| Secondary | 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. | 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 | Posted | Number | µmol/mL | 2 hours post-dose |
|
|
|
| Secondary | 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. | 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 | Posted | Median | Full Range | µM | 2 hours post-dose |
|
|
|
| Secondary | 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. | 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 | Posted | Median | Full Range | µM | 2 hours post-dose |
|
|
|
| Secondary | 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. | 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 | Posted | Median | Full Range | mg/mL | 2 hours post-dose |
|
|
|
| Secondary | 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. | 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 | Posted | Median | Full Range | mg/mL | 2 hours post-dose |
|
|
|
| Secondary | 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). | 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 | Posted | Mean | Standard Deviation | Score on a scale | 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 |
|
|
|
| Secondary | 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). | 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 | Posted | Mean | Standard Deviation | Score on a scale | 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 |
|
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| Secondary | 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). | 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 | Posted | Mean | Standard Deviation | Score on a scale | At the end of a 4-hour post-dose observation period; at the end of a 24-hour observation period on Day 2 |
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| Secondary | 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). | 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 | Posted | Mean | Standard Deviation | Score on a scale | 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 |
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| Secondary | 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. | 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 | Posted | Mean | Standard Deviation | coughs/hour | From start of challenge (2 hours post-dose) to bedtime; up to 12 hours |
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| Secondary | 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. | 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 | Posted | Mean | Standard Deviation | coughs/hour | From start of challenge (2 hours post-dose) to bedtime; up to 12 hours |
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| Secondary | 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. | All randomized participants who received at least 1 dose of study medication | Posted | Number | Percentage of participants | Up to Day 41 |
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| Secondary | 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. | All randomized participants who received at least 1 dose of study medication | Posted | Number | Percentage of participants | Up to Day 24 |
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| 0 |
| 14 |
| 0 |
| 14 |
| 14 |
| 14 |
| EG001 | Cohort 1: Placebo/Healthy | Healthy participants in Cohort 1 who received single doses of placebo | 0 | 14 | 0 | 14 | 5 | 14 |
| EG002 | Cohort 1: Gefapixant 300 mg/Chronic Cough | Participants with chronic cough in Cohort 1 who received single doses of gefapixant 300 mg | 0 | 12 | 0 | 12 | 12 | 12 |
| EG003 | Cohort 1: Placebo/Chronic Cough | Participants with chronic cough in Cohort 1 who received single doses of placebo | 0 | 12 | 0 | 12 | 7 | 12 |
| EG004 | Cohort 2: Gefapixant 50 mg/Healthy | Healthy participants in Cohort 2 who received single doses of gefapixant 50 mg | 0 | 12 | 0 | 12 | 9 | 12 |
| EG005 | Cohort 2: Placebo/Healthy | Healthy participants in Cohort 2 who received single doses of placebo | 0 | 12 | 0 | 12 | 4 | 12 |
| EG006 | Cohort 2: Gefapixant 50 mg/Chronic Cough | Participants with chronic cough in Cohort 2 who received single doses of gefapixant 50 mg | 0 | 12 | 0 | 12 | 6 | 12 |
| EG007 | Cohort 2: Placebo/Chronic Cough | Participants with chronic cough in Cohort 2 who received single doses of placebo | 0 | 11 | 0 | 11 | 3 | 11 |
| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Hypoaesthesia oral | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Paraesthesia oral | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Reflux gastritis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Salivary hypersecretion | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Tongue coated | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Tooth deposit | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Chest discomfort | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Pain | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Oral herpes | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Arthropod bite | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Excoriation | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Spinal osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Ageusia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Hypogeusia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| VIIth Nerve Paralysis | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Dry throat | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Oropharyngeal discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Pharyngeal hypoaesthesia | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Wheezing | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Hot flush | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
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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).
| D012816 |
| Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Day 2 |
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