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

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

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.

Study Overview

• Status: Completed
• Conditions: Refractory Chronic Cough
• Intervention / Treatment: Drug: Placebo; Drug: Gefapixant

Detailed Description

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

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

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

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Afferent Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2015
• Primary Completion (Actual): April 22, 2016
• Study Completion (Actual): May 16, 2016

Study Registration Dates

• First Submitted: March 9, 2015
• First Submitted That Met QC Criteria: March 19, 2015
• First Posted (Estimate): March 25, 2015

Study Record Updates

• Last Update Posted (Actual): February 12, 2021
• Last Update Submitted That Met QC Criteria: January 26, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Cough
• Other Study ID Numbers: 7264-015; AF-219-015 (Other Identifier: Afferent Protocol Number); MK-7264-015 (Other Identifier: Merck Protocol Number); 2015-000464-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf