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Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014)

Primary Purpose

Refractory Chronic Cough

Status

Completed

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Gefapixant 100 mg

Placebo

About this trial

This is an interventional treatment trial for Refractory Chronic Cough

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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 kg/m^2;
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;
Be non-smokers for at least 5 years;
If a female of child-bearing potential (I. e., have not undergone a hysterectomy or bilateral oophorectomy) or not post-menopausal (defined as no menses for at least 12 months), agree to use 2 forms of acceptable birth control; or if a male, they and/or their partner of child-bearing potential agree to use 2 forms of acceptable birth control;
Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions.
Subjects with chronic cough must have treatment-refractory chronic cough for at least one year, with no objective evidence of an underlying trigger (e. g., asthma)

Exclusion Criteria:

History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0);
Have acute worsening of asthma;
Do not cough during the ATP or Capsaicin or Citric acid challenge at Screening or only cough twice at the two highest concentrations of the test solution;
History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with <3 excised basal cell carcinomas);
History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years;
Clinically significant abnormal electrocardiogram (ECG) at Screening;
Significantly abnormal laboratory tests at Screening;
Pregnant or breastfeeding;
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, in the judgment of the Investigator or Sponsor, would make the subject inappropriate for entry into this trial.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Placebo then gefapixant 100 mg/Healthy (Sequence A)

Gefapixant 100 mg then placebo/Healthy (Sequence B)

Placebo then gefapixant 100 mg/Chronic Cough (Sequence A)

Gefapixant 100 mg then placebo/Chronic Cough (Sequence B)

Arm Description

Healthy participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of gefapixant 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

Healthy participants in Sequence B received a single dose of gefapixant 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

Chronic Cough participants in Sequence A received a single dose of placebo in treatment Period 1 then a single dose of gefapixant 100 mg in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

Chronic Cough participants in Sequence B received a single dose of gefapixant 100 mg in treatment Period 1 then a single dose of placebo in treatment Period 2. There was a minimum 48-hr washout between Periods 1 & 2.

Outcomes

Primary Outcome Measures

Cough Reflex Sensitivity to Capsaicin in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

The concentration of capsaicin inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of capsaicin for cough challenge were 0.3 micromoles (µM), 1 µM, 3 µM, 10 µM, 30 µM, 100 µM, 300 µM, and 1000 µM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of capsaicin with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

Cough Reflex Sensitivity to Citric Acid in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

The concentration of citric acid inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of citric acid for cough challenge were 1 millimoles (mM), 3 mM, 10 mM, 30 mM, 100 mM, 300 mM, 1 M, and 3 M. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of citric acid with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

Cough Reflex Sensitivity to ATP in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

The concentration of ATP inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of ATP for cough challenge were 0.1 mM, 0.3 mM, 1 mM, 3 mM, 10 mM, 30 mM, 100 mM, and 300 mM. The Measure Type is least-squares mean in natural log scale. The challenge agent was prepared by dilution of ATP with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

Cough Reflex Sensitivity to Distilled Water in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

The concentration of distilled water inducing at least 2 coughs (C2) and at least 5 coughs (C5) was assessed at 1, 3, and 5 hours post-dose in healthy and chronic cough participants. The concentrations of distilled water for cough challenge were 20%, 40%, 60%, 80%, and 100%. The Measure Type is least-squares mean in natural log scale. The number of coughs generated in 1 minute of exposure was recorded. The challenge agent was prepared by dilution of distilled water with saline, and was administered by inhalation. A mixed effects model used natural log-transformed values for the lowest concentrations of inhaled solution required to evoke at least 2 (C2) or at least 5 (C5) coughs to estimate the average of C2 or C5 across 3 time points for each treatment group, and to compare treatment difference relative to placebo. When applying the mixed model repeated measure analysis, if there is a missing value for concentration, it was imputed as 1.5 times the maximum concentration (=150%).

Secondary Outcome Measures

Change From Baseline in Cough Severity Visual Analogue Scale (VAS) After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

Chronic cough participants completed a visual analogue scale (VAS) to record cough severity, prior to dosing on the treatment day in each treatment period, and one hour after the final cough challenge on the treatment days. This was a 100mm VAS of cough severity from 'No Cough' (0) up to 'Worst Cough' (100). Participants were instructed to draw a line on the scale to indicate how severe they felt their cough was during the previous 1 hour on the treatment days. A negative change from Baseline was considered to indicate improvement in cough severity.

Change From Baseline in Urge to Cough VAS After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

Chronic cough participants completed a VAS to record the severity of their urge to cough, prior to dosing on the treatment day in each treatment period, and one hour after the final cough challenge on the treatment days. Participants marked the 100mm VAS at the extremes as 'No urge-to-cough' (0) and 'Worst urge-to-cough' (100). Participants were instructed to draw a single vertical line on the scale to indicate how severe their urge to cough was during the previous 1 hour on the treatment days. A negative change from Baseline was considered to indicate improvement in urge to cough.

Change From Baseline in Cough Frequency After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

An ambulatory cough recording device recorded all sounds chronic cough participants made during cough monitoring to measure the change from baseline in objective cough frequency on the treatment days. A negative change from Baseline was considered to indicate improvement in cough frequency

Percentage of Participants Who Experienced One or More Adverse Events During Study Treatment and Follow up

A secondary endpoint of the trial was the percentage of participants receiving gefapixant 100 mg and placebo who had at least 1 adverse event (AE) over 4 days of treatment (including washout periods) in addition to 14 days (+3 days) until a post-treatment follow-up visit. An AE is defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with this treatment. Any worsening of a preexisting condition that is temporally associated with the use of the study drug is also an AE. The percentage of participants in any treatment group with at least 1 AE was assessed.

Percentage of Participants Who Discontinued From the Study Due to an Adverse Event

A secondary endpoint of the trial was the percentage of participants receiving gefapixant 100 mg and placebo who discontinued from the study due to an AE. The percentage of participants who discontinued from the study due to an AE was assessed for days 1-4.

Full Information

NCT ID

NCT02476890

First Posted

June 15, 2015

Last Updated

June 10, 2019

Sponsor

Afferent Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02476890

Brief Title

Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014)

Official Title

A Study to Assess the Effect of MK-7264 (AF-219) on Cough Reflex Sensitivity in Both Healthy and Chronic Cough Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

October 28, 2015 (Actual)

Primary Completion Date

October 20, 2016 (Actual)

Study Completion Date

October 20, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Afferent Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The primary objective of this study was to assess the effect of a single dose of gefapixant 100 mg on cough reflex sensitivity to various challenge agents (capsaicin, citric acid, adenosine triphosphate [ATP], and distilled water) in healthy and chronic cough participants.

Detailed Description

The study had a Screening period to determine participant inclusion, two Baseline Visits, and two treatment periods with a minimum 48-hour washout between the treatment periods. At Baseline and during each treatment period, cough sensitivity was measured by standard clinical methodology incorporating four cough challenges. Daytime cough monitoring was performed at Baseline and during each of the two treatment periods (chronic cough participants only).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Refractory Chronic Cough

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Model Description

Chronic cough and healthy participants were randomly assigned to receive gefapixant and placebo in one of two treatment sequences: Sequence A (placebo in treatment period 1, then gefapixant in treatment period 2) or Sequence B (gefapixant in treatment period 1, then placebo in treatment period 2). There was at least a 48-hour washout between the treatment periods. Daytime cough monitoring was performed in chronic cough participants only.

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo then gefapixant 100 mg/Healthy (Sequence A)

Arm Type

Experimental

Arm Description

Arm Title

Gefapixant 100 mg then placebo/Healthy (Sequence B)

Arm Type

Experimental

Arm Description

Arm Title

Placebo then gefapixant 100 mg/Chronic Cough (Sequence A)

Arm Type

Experimental

Arm Description

Arm Title

Gefapixant 100 mg then placebo/Chronic Cough (Sequence B)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Gefapixant 100 mg

Other Intervention Name(s)

MK-7264, AF-219

Intervention Description

Gefapixant 100 mg (2 x 50 mg tablets), administered orally as a single dose in treatment Period 1 or treatment Period 2

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo (two tablets matching gefapixant 50 mg), administered orally as a single dose in treatment Period 1 or treatment Period 2

Primary Outcome Measure Information:

Title

Cough Reflex Sensitivity to Capsaicin in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

Description

Time Frame

Average of 1, 3, and 5 hours post-dose

Title

Cough Reflex Sensitivity to Citric Acid in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

Description

Time Frame

Average of 1, 3, and 5 hours post-dose

Title

Cough Reflex Sensitivity to ATP in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

Description

Time Frame

Average of 1, 3, and 5 hours post-dose

Title

Cough Reflex Sensitivity to Distilled Water in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined)

Description

Time Frame

Average of 1, 3, and 5 hours post-dose

Secondary Outcome Measure Information:

Title

Change From Baseline in Cough Severity Visual Analogue Scale (VAS) After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

Description

Time Frame

Baseline and one hour after the final cough challenge on treatment days

Title

Change From Baseline in Urge to Cough VAS After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

Description

Time Frame

Baseline and one hour after final cough challenge on treatment days

Title

Change From Baseline in Cough Frequency After Cough Challenge Testing in Participants Who Received Gefapixant 100 mg and Placebo (Chronic Cough Participants Only)

Description

Time Frame

Baseline and for 24 hours after cough challenge on treatment days

Title

Percentage of Participants Who Experienced One or More Adverse Events During Study Treatment and Follow up

Description

Time Frame

Up to Day 18

Title

Percentage of Participants Who Discontinued From the Study Due to an Adverse Event

Description

Time Frame

Up to Day 4

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 kg/m^2; 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; Be non-smokers for at least 5 years; If a female of child-bearing potential (I. e., have not undergone a hysterectomy or bilateral oophorectomy) or not post-menopausal (defined as no menses for at least 12 months), agree to use 2 forms of acceptable birth control; or if a male, they and/or their partner of child-bearing potential agree to use 2 forms of acceptable birth control; Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions. Subjects with chronic cough must have treatment-refractory chronic cough for at least one year, with no objective evidence of an underlying trigger (e. g., asthma) Exclusion Criteria: History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0); Have acute worsening of asthma; Do not cough during the ATP or Capsaicin or Citric acid challenge at Screening or only cough twice at the two highest concentrations of the test solution; History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with <3 excised basal cell carcinomas); History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years; Clinically significant abnormal electrocardiogram (ECG) at Screening; Significantly abnormal laboratory tests at Screening; Pregnant or breastfeeding; 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, in the judgment of the Investigator or Sponsor, would make the subject inappropriate for entry into this trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Merck Sharp & Dohme LLC

Official's Role

Study Director

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Citations:

PubMed Identifier

31023843

Citation

Morice AH, Kitt MM, Ford AP, Tershakovec AM, Wu WC, Brindle K, Thompson R, Thackray-Nocera S, Wright C. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019 Jul 4;54(1):1900439. doi: 10.1183/13993003.00439-2019. Print 2019 Jul.

Results Reference

result

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Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014)

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