A Study to Assess the Efficacy of Gefapixant (MK-7264/AF-219), in Participants With Chronic Cough (MK-7264-006)

A Study to Assess the Efficacy of AF-219, a P2X3 Receptor Antagonist, in Subjects With Chronic Cough (EPiCC)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01432730

Acronym

EPICC

Enrollment

Registered

2011-09-13

Start date

2011-09-22

Completion date

2013-02-21

Last updated

2020-11-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Cough

Brief summary

This is a randomised, double-blind, placebo-controlled, crossover, single centre study of gefapixant (AF-219/MK-7264) in participants with idiopathic or treatment resistant chronic cough designed to evaluate the effectiveness of gefapixant in reducing daytime objective cough frequency.

Interventions

DRUGGefapixant

Oral tablets, BID

DRUGPlacebo

Oral tablets, BID

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

* History of cough for more than 8 weeks * Normal chest radiograph * Idiopathic or treatment resistant cough (idiopathic defined as a cough for which no objective evidence of an underlying trigger can be determined after investigation or a cough that is unresponsive to 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip \[treatment-resistant\]).

Exclusion criteria

* Current smoker * Individuals who have given up smoking within the past 6 months, or those with \>20 pack-year smoking history * Treatment with an angiotensin-converting-enzyme inhibitor (ACE-inhibitor) as the potential cause of a participant's cough, or requiring treatment with an ACE-inhibitor during the study or within 4 weeks prior to Day 0 * Forced Expiratory Volume (FEV1)/Forced Vital Capacity (FVC) \<60%

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Daytime Objective Cough Frequency	Baseline (Day 0) and Day 14 of each study period	Daytime Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participants is awake. 24-hour sound recordings were collected using a digital recording device. Change from baseline in awake cough frequency = (post-treatment awake cough frequency - baseline awake cough frequency). A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Secondary

Measure	Time frame	Description
Change From Baseline in Nighttime Objective Cough Frequency	Baseline (Day 0) and Day 14 of each study period	Nighttime Objective Cough Frequency = Total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24 hour sound recording were collected with a digital recording device. Change from baseline in nighttime cough frequency = (post-treatment nighttime cough frequency - baseline nighttime cough frequency). A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Change From Baseline of Daytime Cough Severity Score Using a Visual Analogue Scale (VAS)	Baseline (Day 0) and Day 15 of each study period	Cough Severity VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough. Change from baseline in daytime cough severity = (post-treatment daytime cough severity - baseline daytime cough severity). A negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
Change From Baseline of Nighttime Cough Severity Score Using a Visual Analogue Scale (VAS)	Baseline (Day 0) and Day 15 of each study period	Cough Severity VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough. Change from baseline in nighttime cough severity = (post-treatment nighttime cough severity - baseline nighttime cough severity). A negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
Change From Baseline of 24-hour Objective Cough Frequency	24 hours at Baseline (Day 0) and Day 14 of each study period	Total (0-24 hours) Objective Cough Frequency = Total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Global Rating of Change Score for Cough Frequency	Day 15 of each study period	At the end of each study period, participants were asked to complete the global rating of change scale questionnaire. The participants were asked to record whether their cough frequency was worse, about the same, or better. If better or worse, the participants were then asked by how much with a 7-category rating scale. Therefore, a 15-point ordered scale was used (1=minimum, a very great deal better to 15=maximum, a very great deal worse with a score of 8=indicating no change).
Global Rating of Change Score for Cough Severity	Day 15 of each study period	At the end of each study period, participants were asked to complete the global rating of change scale questionnaire. The participants were asked to record whether their cough severity was worse, about the same, or better. If better or worse, the participants were then asked by how much with a 7-category rating scale. Therefore, a 15-point ordered scale was used (1=minimum, a very great deal better to 15=maximum, a very great deal worse with a score of 8=indicating no change).
Change From Baseline in Cough-specific Quality of Life Questionnaire (CQLQ)	Baseline (Day 0) and Day 15 of each study period	The CQLQ Questionnaire included 28 items that described negative aspects of quality of life specific to chronic cough. Subscales include: Physical complaints, Psychosocial issues, Functional abilities, Emotional wellbeing, Extreme physical complaints, and Personal safety fears. Participants indicated their degree of agreement with each statement on a 4 point scale (1 = strongly disagree; 2 = disagree; 3 = agree; 4 = strongly agree). CQLQ scores (28 for least impact, 112 for highest impact) used a mixed effect model with terms for treatment sequence, participant within sequence, treatment, and period. Change from baseline in CQLQ scores = (posttreatment CQLQ scores - baseline CQLQ scores). A negative result indicates a decrease in CQLQ scores (lowest cough impact on health-related quality of life), while a positive result indicates an increase in CQLQ scores (highest cough impact on health-related quality of life).
Change From Baseline in Urge to Cough Questionnaire (UtCQ) 100 mm Visual Analogue Scale	Baseline (Day 0) and Day 15 of each study period	UtCQ is determined through the use of a 100mm visual analogue scale (VAS) (ranging between 0 for no urge to cough and 100 for severe urge to cough). Change from baseline in UtCQ scores = (post-treatment UtCQ scores - baseline UtCQ scores). A negative result indicates a decrease in UtCQ scores (lowest impact), while a positive result indicates an increase in UtCQ scores (highest impact).

Other

Measure	Time frame	Description
Baseline Nighttime Objective Cough Frequency	Baseline (Day 0) of each study period	Nighttime Objective Cough Frequency is the total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24 hour sound recording were collected with a digital recording device.
Baseline Nighttime Cough Severity Score Using a Visual Analogue Scale (VAS)	Baseline (Day 0) of each study period	Nighttime cough severity was scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough.
Baseline 24-Hour Objective Cough Frequency	Baseline (Day 0) of each study period	Total (0-24 hours) Objective Cough Frequency = Total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device.
Baseline Cough-specific Quality of Life Questionnaire (CQLQ)	Baseline (Day 0) of each study period	The CQLQ Questionnaire included 28 items that described negative aspects of quality of life specific to chronic cough. Subscales include: Physical complaints, Psychosocial issues, Functional abilities, Emotional wellbeing, Extreme physical complaints, and Personal safety fears. Participants indicated their degree of agreement with each statement on a 4 point scale (1 = strongly disagree; 2 = disagree; 3 = agree; 4 = strongly agree). CQLQ scores (28 for least impact, 112 for highest impact) used a mixed effect model with terms for treatment sequence, participant within sequence, treatment, and period. Change from baseline in CQLQ scores = (posttreatment CQLQ scores - baseline CQLQ scores). A negative result indicates a decrease in CQLQ scores (lowest cough impact on health-related quality of life), while a positive result indicates an increase in CQLQ scores (highest cough impact on health-related quality of life).
Baseline Urge to Cough Questionnaire (UtCQ) 100 mm Visual Analogue Scale	Baseline (Day 0) of each study period	UtCQ is determined through the use of a 100mm visual analogue scale (VAS) (ranging between 0 for no urge to cough and 100 for severe urge to cough).
Baseline Daytime Cough Severity Score Using a Visual Analogue Scale (VAS)	Baseline (Day 0) of each study period	Cough Severity VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough.
Baseline Daytime Cough Frequency	Baseline (Day 0) of each study period	Daytime Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participants is awake. 24-hour sound recordings were collected using a digital recording device.

Participant flow

Recruitment details

24 participants were enrolled and randomized from a single center.

Participants by arm

Arm	Count
All Participants Gefapixant, 600 mg, BID, taken orally for 2 weeks in Period 1 followed by a 2-week washout period and then placebo to gefapixant, BID, taken orally for 2 weeks in Period 2 OR Placebo to gefapixant, BID, taken orally for 2 weeks in Period 1 followed by a 2-week washout period and then gefapixant, 600 mg, BID, taken orally for 2 weeks in Period 2	24
Total	24

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1	Adverse Event	2	0
Period 2	Adverse Event	0	4

Baseline characteristics

Characteristic	All Participants
Age, Continuous	54.5 Years STANDARD_DEVIATION 11.1
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	24 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	24 Participants
Sex: Female, Male Female	18 Participants
Sex: Female, Male Male	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	24 / 24	5 / 22
serious Total, serious adverse events	0 / 24	0 / 22

Outcome results

Primary

Change From Baseline in Daytime Objective Cough Frequency

Daytime Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participants is awake. 24-hour sound recordings were collected using a digital recording device. Change from baseline in awake cough frequency = (post-treatment awake cough frequency - baseline awake cough frequency). A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Time frame: Baseline (Day 0) and Day 14 of each study period

Population: Analysis population consisted of all participants for Periods 1 and 2 who were randomized, received at least 1 dose of study drug, were compliant with the study procedure and had available data for this outcome measure.

Arm	Measure	Value (LOG_MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline in Daytime Objective Cough Frequency	-0.5365 Coughs/hour	Standard Error 0.1718
Placebo	Change From Baseline in Daytime Objective Cough Frequency	0.0523 Coughs/hour	Standard Error 0.0462

p-value: 0.000395% CI: [-0.9049, -0.3005]Mixed Models Analysis

Secondary

Change From Baseline in Cough-specific Quality of Life Questionnaire (CQLQ)

The CQLQ Questionnaire included 28 items that described negative aspects of quality of life specific to chronic cough. Subscales include: Physical complaints, Psychosocial issues, Functional abilities, Emotional wellbeing, Extreme physical complaints, and Personal safety fears. Participants indicated their degree of agreement with each statement on a 4 point scale (1 = strongly disagree; 2 = disagree; 3 = agree; 4 = strongly agree). CQLQ scores (28 for least impact, 112 for highest impact) used a mixed effect model with terms for treatment sequence, participant within sequence, treatment, and period. Change from baseline in CQLQ scores = (posttreatment CQLQ scores - baseline CQLQ scores). A negative result indicates a decrease in CQLQ scores (lowest cough impact on health-related quality of life), while a positive result indicates an increase in CQLQ scores (highest cough impact on health-related quality of life).

Time frame: Baseline (Day 0) and Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline in Cough-specific Quality of Life Questionnaire (CQLQ)	-10.8 Score on a scale	Standard Deviation 14.23
Placebo	Change From Baseline in Cough-specific Quality of Life Questionnaire (CQLQ)	-1.4 Score on a scale	Standard Deviation 6.48

p-value: 0.01895% CI: [-16.759, -1.716]Mixed Models Analysis

Secondary

Change From Baseline in Nighttime Objective Cough Frequency

Nighttime Objective Cough Frequency = Total number of cough events during the monitoring period the participant is asleep divided by the total duration (in hours) for the monitoring period the participant is asleep. 24 hour sound recording were collected with a digital recording device. Change from baseline in nighttime cough frequency = (post-treatment nighttime cough frequency - baseline nighttime cough frequency). A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Time frame: Baseline (Day 0) and Day 14 of each study period

Arm	Measure	Value (LOG_MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline in Nighttime Objective Cough Frequency	-0.3452 Coughs/hour	Standard Error 0.2314
Placebo	Change From Baseline in Nighttime Objective Cough Frequency	0.0690 Coughs/hour	Standard Error 0.1767

p-value: 0.05795% CI: [-0.8568, 0.01438]Mixed Models Analysis

Secondary

Change From Baseline in Urge to Cough Questionnaire (UtCQ) 100 mm Visual Analogue Scale

UtCQ is determined through the use of a 100mm visual analogue scale (VAS) (ranging between 0 for no urge to cough and 100 for severe urge to cough). Change from baseline in UtCQ scores = (post-treatment UtCQ scores - baseline UtCQ scores). A negative result indicates a decrease in UtCQ scores (lowest impact), while a positive result indicates an increase in UtCQ scores (highest impact).

Time frame: Baseline (Day 0) and Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline in Urge to Cough Questionnaire (UtCQ) 100 mm Visual Analogue Scale	-27.2 Score on a scale	Standard Deviation 42.07
Placebo	Change From Baseline in Urge to Cough Questionnaire (UtCQ) 100 mm Visual Analogue Scale	-6.5 Score on a scale	Standard Deviation 28.59

p-value: 0.03595% CI: [-40.96, -1.54]Mixed Models Analysis

Secondary

Change From Baseline of 24-hour Objective Cough Frequency

Total (0-24 hours) Objective Cough Frequency = Total number of cough events during the monitoring period divided by the total duration (in hours, i.e., 24 hours mostly) for the monitoring period. 24-hour sound recordings were collected using a digital recording device. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

Time frame: 24 hours at Baseline (Day 0) and Day 14 of each study period

Arm	Measure	Value (LOG_MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline of 24-hour Objective Cough Frequency	-0.5562 Coughs/hour	Standard Error 0.1795
Placebo	Change From Baseline of 24-hour Objective Cough Frequency	0.0298 Coughs/hour	Standard Error 0.0459

p-value: 0.00195% CI: [-0.8934, -0.2707]Mixed Models Analysis

Secondary

Change From Baseline of Daytime Cough Severity Score Using a Visual Analogue Scale (VAS)

Cough Severity VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough. Change from baseline in daytime cough severity = (post-treatment daytime cough severity - baseline daytime cough severity). A negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.

Time frame: Baseline (Day 0) and Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline of Daytime Cough Severity Score Using a Visual Analogue Scale (VAS)	-21.5 Score on a scale	Standard Deviation 35.65
Placebo	Change From Baseline of Daytime Cough Severity Score Using a Visual Analogue Scale (VAS)	-0.7 Score on a scale	Standard Deviation 19.01

p-value: 0.00395% CI: [-41.53, -9.62]Mixed Models Analysis

Secondary

Change From Baseline of Nighttime Cough Severity Score Using a Visual Analogue Scale (VAS)

Cough Severity VAS: scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 100mm with 0 representing no cough and 100 the most severe cough. Change from baseline in nighttime cough severity = (post-treatment nighttime cough severity - baseline nighttime cough severity). A negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.

Time frame: Baseline (Day 0) and Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Change From Baseline of Nighttime Cough Severity Score Using a Visual Analogue Scale (VAS)	-16.1 Score on a scale	Standard Deviation 27.71
Placebo	Change From Baseline of Nighttime Cough Severity Score Using a Visual Analogue Scale (VAS)	-3.7 Score on a scale	Standard Deviation 22.05

p-value: 0.17295% CI: [-20.93, 3.87]Mixed Models Analysis

Secondary

Global Rating of Change Score for Cough Frequency

At the end of each study period, participants were asked to complete the global rating of change scale questionnaire. The participants were asked to record whether their cough frequency was worse, about the same, or better. If better or worse, the participants were then asked by how much with a 7-category rating scale. Therefore, a 15-point ordered scale was used (1=minimum, a very great deal better to 15=maximum, a very great deal worse with a score of 8=indicating no change).

Time frame: Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Global Rating of Change Score for Cough Frequency	5.83 Score on a scale	Standard Deviation 4.96
Placebo	Global Rating of Change Score for Cough Frequency	8.32 Score on a scale	Standard Deviation 2.28

p-value: 0.03395% CI: [-4.849, -0.227]Mixed Models Analysis

Secondary

Global Rating of Change Score for Cough Severity

At the end of each study period, participants were asked to complete the global rating of change scale questionnaire. The participants were asked to record whether their cough severity was worse, about the same, or better. If better or worse, the participants were then asked by how much with a 7-category rating scale. Therefore, a 15-point ordered scale was used (1=minimum, a very great deal better to 15=maximum, a very great deal worse with a score of 8=indicating no change).

Time frame: Day 15 of each study period

Arm	Measure	Value (MEAN)	Dispersion
Gefapixant 600 mg	Global Rating of Change Score for Cough Severity	6.00 Score on a scale	Standard Deviation 4.94
Placebo	Global Rating of Change Score for Cough Severity	8.23 Score on a scale	Standard Deviation 2.25

p-value: 0.04995% CI: [-4.523, -0.01]Mixed Models Analysis

Other Pre-specified