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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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A Study to Assess the Effect of AF-219 on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects

Conditions
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Refractory Chronic Cough

Intervention / Treatment
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* Drug: Gefapixant
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefapixant 50 mg<br>Gefapixant 50 mg (1 tablet) administered as a single dose | Drug: Gefapixant<br>* Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets)<br>* Other names: MK-7264;|
| Experimental: Gefapixant 300 mg<br>Gefapixant 300 mg (6 tablets) administered as a single dose | Drug: Gefapixant<br>* Gefapixant tablets administered orally as a single dose of 50 mg (1 tablet) or 300 mg (6 tablets)<br>* Other names: MK-7264;|
| Placebo Comparator: Placebo<br>Placebo-matching tablets administered as a single dose | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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 |