Refractory Chronic CoughPhase 2NCT02349425

A Dose Escalation Study of Gefapixant (AF-219/MK-7264) in Refractory Chronic Cough (MK-7264-010)

A Phase 2 study testing Gefapixant in people with Refractory Chronic Cough, run by Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

A randomized, double-blind, placebo-controlled, crossover, dose escalation study to assess the efficacy and tolerability of gefapixant (AF-219; MK-7264) in participants with refractory chronic cough. Read more about this study

Who is it for?: Ages 18 to 80 years
Conditions the study is for: Refractory Chronic Cough
What is being tested?: Gefapixant
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 59 participants
Where: No sites listed yet
Study dates: 9 Mar 2015to 9 Feb 2016
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Chest radiograph or computed tomography (CT) thorax within the last 12 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough
Refractory chronic cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip or unexplained cough: a cough for which no objective evidence of an underlying trigger can be determined after investigation
Score of ≥ 40 mm on the Cough Severity Visual Analog Scale (VAS) at Screening
Women of child-bearing potential must use 2 forms of acceptable birth control method from Screening through the Follow-Up Visit.
Male participants and their partners of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug.
Written informed consent.
Willing and able to comply with all aspects of the protocol.

Who cannot join

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 (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 the Baseline Visit (Day 0)
Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 60%
History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0)
History of opioid use within 1 week of the Baseline Visit (Day 0)

Show all 20Show fewer

Requiring concomitant therapy with prohibited medications
Body mass index (BMI) <18 kg/m^2 or ≥ 37 kg/m^2
History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including participants with <3 excised basal cell carcinomas)
History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years
Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection)
Screening systolic blood pressure (SBP) >160 mmHg or a diastolic blood pressure (DBP) >90 mmHg
Clinically significant abnormal electrocardiogram (ECG) at Screening
Personal or family history of congenital long QT syndrome or family history of sudden death
Cardiac pacemaker
Significantly abnormal laboratory tests at Screening
Breastfeeding
Treatment with an investigational drug (except gefapixant) or biologic within 60 days preceding the first dose of study medication or plans to take another investigational drug or biologic within 30 days of study completion
Blood donation within 56 days or plasma donation within 7 days prior to dosing
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

About this study

Official title: A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects With Refractory Chronic Cough

A randomized, double-blind, placebo-controlled, crossover, dose escalation study to assess the efficacy and tolerability of gefapixant (AF-219; MK-7264) in participants with refractory chronic cough.

Conditions: Refractory Chronic Cough
Being tested: Gefapixant, Placebo (for gefapixant)
Medical subject headings: Chronic Cough

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

GefapixantDrug
Also called AF-219, MK-7264
Gefapixant 7.5 and 50mg tablets administered orally
Placebo (for gefapixant)Drug
Placebo to gefapixant 7.5 and 50mg tablets administered orally

Study groups in NCT02349425
Study group	Role	What they receive
Cohort 1: Gefapixant>Placebo	Experimental	50, 100, 150, and 200 mg gefapixant twice daily (BID) for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods. Receives: Drug: Gefapixant; Drug: Placebo (for gefapixant)
Cohort 1: Placebo>Gefapixant	Experimental	Placebo BID for 16 days in Period 1 and gefapixant 50, 100, 150, and 200 mg BID for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods. Receives: Drug: Gefapixant; Drug: Placebo (for gefapixant)
Cohort 2: Gefapixant>Placebo	Experimental	Gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods. Receives: Drug: Gefapixant; Drug: Placebo (for gefapixant)
Cohort 2: Placebo>Gefapixant	Experimental	Placebo BID for 16 days in Period 1 and gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods. Receives: Drug: Gefapixant; Drug: Placebo (for gefapixant)

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
Awake Objective 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 participant is awake. 24-hour sound recordings were collected using a digital recording device.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
Awake Objective 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 participant is awake. 24-hour sound recordings were collected using a digital recording device.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Percent Change From Baseline in Awake Cough Frequency for Cohort 1
Awake 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 participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Percent Change From Baseline in Awake Cough Frequency for Cohort 2
Awake 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 participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Responder Analysis of Awake Cough Frequency for Cohort 1
Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Responder Analysis of Awake Cough Frequency for Cohort 2
Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.
Measured: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Secondary outcomes (11)

Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1
Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2
Awake (0-8 hours) Objective Cough Frequency is the total number of cough events during the monitoring period the participant was awake for the first 8 hours after the participant took their study medication divided by 8 or the total duration (in hours) for the monitoring period the participant was awake whichever is less. 24-hour sound recordings were collected using a digital recording device. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using a mixed model repeated measures (MMRM) to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1
Total (0-24 hours) Objective Cough Frequency is the 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. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2
Total (0-24 hours) Objective Cough Frequency is the 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. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Sleep Cough Frequency - Cohort 1
Sleep 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. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Sleep Cough Frequency - Cohort 2
Sleep 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. Results are change from baseline: a negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Cough frequency was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1
The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2
The daily CSD Score is calculated using the daily CSD instrument, a 7-item, disease specific, patient-reported outcome measure with a recall period of "today" (the current day). The measure evaluates frequency of cough (3 items); intensity of cough (2 items); and sleep disruption due to cough (2 items). Each of these 7 items is rated on an 11-point scale, ranging from 0 (best) to 10 (worst), with higher scores indicating greater severity. The total daily CSD score is the sum of these 7 item scores (Min=0, Max=70). Baseline CSD score = average of CSD scores at screening and baseline. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
CSD was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2
The LCQ-Acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for acute cough which contains three domains (i.e., physical, psychological, and social). It is calculated as a mean score for each domain ranging from 1 (worst) to 7 (best), and total score ranging from 3 (worst) to 21 (best). Each item on the LCQ-acute assesses symptoms or the impact of symptoms on HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. Participants' perception of their cough severity was assessed, based on the LCQ-Acute score, at Baseline and last day of dose.
LCQ was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1
Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2
Cough VAS is scored from 0 to 100 using a 10 mm visual analogue scale with 0 at 0mm and 100 at 10mm with 0 (no cough) and 100 (most severe cough). Baseline cough VAS is defined as average of screening and baseline cough VAS. Results are change from baseline: a negative result indicates a decrease in cough severity, while a positive result indicates an increase in cough severity.
Cough VAS was analyzed using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures.
Measured: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

9 Mar 20159 Feb 2016

First posted28 Jan 2015 (estimated)
Study start9 Mar 2015
Primary completion1 Feb 2016
Study completion9 Feb 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Refractory Chronic CoughStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 59 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02349425
Sponsor's protocol ID: 7264-010
Other IDs: AF219-010, MK-7264-010, 2015-000474-35, 2015
Status last verified: Sep 2020
First submitted: 23 Jan 2015
Last updated: 22 Oct 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Publications

LATE-BREAKING ABSTRACT: Tackling the burden of chronic cough: A dose escalation study of AF-219 Jaclyn Smith, Michael Kitt, Mandel Sher, Peter Butera, Anthony Ford European Respiratory Journal 2016 48: OA1976; DOI: 10.1183/13993003.congress-2016.OA1976
Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, Holt K, Sen S, Sher MR, Ford AP. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020 Mar 20;55(3):1901615. doi: 10.1183/13993003.01615-2019. Print 2020 Mar.
PubMed 31949115

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

RecruitingPhase 2
The Effect of Nalbuphine Extended-Release (NAL ER) on Cough in Participants With Refractory Chronic Cough (RCC)
Refractory Chronic Cough
Not yet recruitingPhase 4
A 2x2 Factorial, Randomized, Open-label Trial to Evaluate Neuromodulators and Cough Control Therapy in Patients With Refractory or Unexplained Chronic Cough
Cough, Refractory Chronic Cough
RecruitingPhase 2
A Study to Investigate the Efficacy and Safety of SC0032, a Magnesium Salt Oral Spray, in Adults With Refractory or Unexplained Chronic Cough
Refractory Chronic Cough and Unexplained Chronic Cough
RecruitingPhase 2
Mechanisms of Change in Behavioral Cough Suppression Therapy for Refractory Chronic Cough
Chronic Cough (CC), Refractory Chronic Cough
Active, not recruitingPhase 3
A 24-Week Study of the Efficacy and Safety of BLU-5937 in Adults With Refractory Chronic Cough
Cough, Refractory Chronic Cough

All Refractory Chronic Cough trials

Study at a glance

From the registry record, last updated by the sponsor on 22 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects With Refractory Chronic Cough
ClinicalTrials.gov ID: NCT02349425
Acronym / sponsor ID: 7264-010
Conditions: Refractory Chronic Cough
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 59 participants (actual)
Lead sponsor: Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)Industry (pharma, biotech, devices)
Study start: 9 Mar 2015 (actual)
Primary completion: 1 Feb 2016 (actual)
Study completion: 9 Feb 2016 (actual)
First posted: 28 Jan 2015 (estimated)
Results: Posted 22 Oct 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

A randomized, double-blind, placebo-controlled, crossover, dose escalation study to assess the efficacy and tolerability of gefapixant (AF-219; MK-7264) in participants with refractory chronic cough.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
Cohort 1: Gefapixant>Placebo	Experimental	Drug: Gefapixant, Drug: Placebo (for gefapixant)50, 100, 150, and 200 mg gefapixant twice daily (BID) for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
Cohort 1: Placebo>Gefapixant	Experimental	Drug: Gefapixant, Drug: Placebo (for gefapixant)Placebo BID for 16 days in Period 1 and gefapixant 50, 100, 150, and 200 mg BID for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.
Cohort 2: Gefapixant>Placebo	Experimental	Drug: Gefapixant, Drug: Placebo (for gefapixant)Gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.
Cohort 2: Placebo>Gefapixant	Experimental	Drug: Gefapixant, Drug: Placebo (for gefapixant)Placebo BID for 16 days in Period 1 and gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.

Who may qualify

Ages: 18 to 80 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

Chest radiograph or computed tomography (CT) thorax within the last 12 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough
Refractory chronic cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip or unexplained cough: a cough for which no objective evidence of an underlying trigger can be determined after investigation
Score of ≥ 40 mm on the Cough Severity Visual Analog Scale (VAS) at Screening
Women of child-bearing potential must use 2 forms of acceptable birth control method from Screening through the Follow-Up Visit.
Male participants and their partners of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug.

Key exclusion criteria (20 listed)

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 (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 the Baseline Visit (Day 0)
Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 60%
History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
GefapixantAlso: AF-219, MK-7264Gefapixant 7.5 and 50mg tablets administered orally	Drug	Cohort 1: Gefapixant>Placebo, Cohort 1: Placebo>Gefapixant, Cohort 2: Gefapixant>Placebo, Cohort 2: Placebo>Gefapixant
Placebo (for gefapixant)Placebo to gefapixant 7.5 and 50mg tablets administered orally	Drug	Cohort 1: Gefapixant>Placebo, Cohort 1: Placebo>Gefapixant, Cohort 2: Gefapixant>Placebo, Cohort 2: Placebo>Gefapixant

Primary outcome

Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Awake Objective 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 participant is awake. 24-hour sound recordings were collected using a digital recording device.
Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Awake Objective 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 participant is awake. 24-hour sound recordings were collected using a digital recording device.
Percent Change From Baseline in Awake Cough Frequency for Cohort 1
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Awake 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 participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Percent Change From Baseline in Awake Cough Frequency for Cohort 2
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Awake 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 participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.
Responder Analysis of Awake Cough Frequency for Cohort 1
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.
Responder Analysis of Awake Cough Frequency for Cohort 2
Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.

11 secondary outcomes

Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1
Time frame: Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2
Time frame: Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1
Time frame: Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2
Time frame: Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Sleep Cough Frequency - Cohort 1
Time frame: Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline in Sleep Cough Frequency - Cohort 2
Time frame: Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1
Time frame: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2
Time frame: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2
Time frame: Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1
Time frame: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2
Time frame: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39

Results and safety

Results posted to the registry on 22 Oct 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Cohort 1: Gefapixant>Placebo	15	14
Cohort 1: Placebo>Gefapixant	14	13
Cohort 2: Gefapixant>Placebo	15	15
Cohort 2: Placebo>Gefapixant	15	15

Primary outcome: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1

Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses. Geometric mean (95% Confidence Interval). Unit: Log coughs/hour

Measure	Cohort 1 - Gefapixant 50 mg n = 26	Cohort 1 - Placebo for Gefapixant 50 mg n = 25	Cohort 1 - Gefapixant 100 mg n = 24	Cohort 1 - Placebo for Gefapixant 100 mg n = 25	Cohort 1 - Gefapixant 150 mg n = 23	Cohort 1 - Placebo for Gefapixant 150 mg n = 22	Cohort 1 - Gefapixant 200 mg n = 25	Cohort 1 - Placebo for Gefapixant 200 mg n = 25
Value	0.56 (0.43 to 0.72)	0.95 (0.73 to 1.23)	0.46 (0.34 to 0.61)	0.95 (0.71 to 1.28)	0.48 (0.35 to 0.65)	0.90 (0.65 to 1.24)	0.45 (0.33 to 0.63)	1.06 (0.75 to 1.48)

Cohort 1 - Gefapixant 50 mg vs Cohort 1 - Placebo for Gefapixant 50 mg: Estimated percent change: -41.222 (95% CI -59.294 to -15.127), p = 0.0055, Mixed Models Analysis
Cohort 1 - Gefapixant 100 mg vs Cohort 1 - Placebo for Gefapixant 100 mg: Estimated percent change: -51.973 (95% CI -68.230 to -27.397), p = 0.0008, Mixed Models Analysis
Cohort 1 - Gefapixant 150 mg vs Cohort 1 - Placebo for Gefapixant 150 mg: Estimated percent change: -46.853 (95% CI -66.291 to -16.206), p = 0.0075, Mixed Models Analysis

Population analysed: Analysis population consisted of all participants in Cohort 1 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.

Primary outcome: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2

Measure	Cohort 2 - Gefapixant 7.5 mg n = 29	Cohort 2 - Placebo for Gefapixant 7.5 mg n = 28	Cohort 2 - Gefapixant 15 mg n = 30	Cohort 2 - Placebo for Gefapixant 15 mg n = 29	Cohort 2 - Gefapixant 30 mg n = 29	Cohort 2 - Placebo for Gefapixant 30 mg n = 29	Cohort 2 - Gefapixant 50 mg n = 29	Cohort 2 - Placebo for Gefapixant 50 mg n = 27
Value	0.80 (0.66 to 0.96)	0.93 (0.77 to 1.13)	0.67 (0.57 to 0.80)	0.90 (0.75 to 1.08)	0.53 (0.40 to 0.69)	0.84 (0.64 to 1.10)	0.44 (0.32 to 0.60)	1.00 (0.72 to 1.38)

Cohort 2 - Gefapixant 7.5 mg vs Cohort 2 - Placebo for Gefapixant 7.5 mg: Estimated percent change: -14.691 (95% CI -35.307 to 12.493), p = 0.2542, Mixed Models Analysis
Cohort 2 - Gefapixant 15 mg vs Cohort 2 - Placebo for Gefapixant 15 mg: Estimated percent change: -25.165 (95% CI -42.014 to -3.4210), p = 0.0267, Mixed Models Analysis
Cohort 2 - Gefapixant 30 mg vs Cohort 2 - Placebo for Gefapixant 30 mg: Estimated percent change: -37.146 (95% CI -57.345 to -7.3821), p = 0.0198, Mixed Models Analysis

Population analysed: Analysis population consisted of all participants in Cohort 2 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.

Primary outcome: Percent Change From Baseline in Awake Cough Frequency for Cohort 1

Time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses. Mean (Standard Deviation). Unit: Percent Change

Measure	Cohort 1 - Gefapixant 50 mg n = 26	Cohort 1' - Placebo for Gefapixant 50 mg n = 25	Cohort 1 - Gefapixant 100 mg n = 24	Cohort 1 - Placebo for Gefapixant 100 mg n = 25	Cohort 1 - Gefapixant 150 mg n = 23	Cohort 1 - Placebo for Gefapixant 150 mg n = 22	Cohort 1 - Gefapixant 200 mg n = 25	Cohort 1 - Placebo for Gefapixant 200 mg n = 25
Value	-20.6 (84.29)	-0.1 (33.75)	-31.7 (70.27)	1.9 (35.18)	-22.0 (82.84)	-0.1 (39.55)	-27.9 (57.03)	15.1 (48.38)

Primary outcome: Percent Change From Baseline in Awake Cough Frequency for Cohort 2

Measure	Cohort 2 - Gefapixant 7.5 mg n = 29	Cohort 2 - Placebo for Gefapixant 7.5 mg n = 28	Cohort 2 - Gefapixant 15 mg n = 30	Cohort 2 - Placebo for Gefapixant 15 mg n = 29	Cohort 2 - Gefapixant 30 mg n = 29	Cohort 2 - Placebo for Gefapixant 30 mg n = 29	Cohort 2 - Gefapixant 50 mg n = 29	Cohort 2 - Placebo for Gefapixant 50 mg n = 27
Value	5.0 (125.05)	-3.8 (36.13)	-21.4 (39.32)	-6.4 (33.78)	-26.3 (61.01)	-1.1 (64.38)	-28.1 (74.90)	23.1 (92.60)

11 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse event data collection is up to 11 weeks All-cause mortality is up to 22 weeks. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1: Gefapixant 50 mg	0 of 28 (0%)	17 of 28 (60.7%)	0 of 28
Cohort 1: Gefapixant 100 mg	1 of 28 (3.6%)	8 of 28 (28.6%)	0 of 28
Cohort 1 - Gefapixant 150 mg	0 of 26 (0%)	4 of 26 (15.4%)	0 of 26
Cohort 1: Gefapixant 200 mg	0 of 26 (0%)	6 of 26 (23.1%)	0 of 26
Cohort 1 - Placebo	1 of 28 (3.6%)	4 of 28 (14.3%)	0 of 28
Cohort 2 - Gefapixant 7.5 mg	0 of 30 (0%)	6 of 30 (20%)	0 of 30
Cohort 2 - Gefapixant 15 mg	0 of 30 (0%)	1 of 30 (3.3%)	0 of 30
Cohort 2 - Gefapixant 30 mg	0 of 30 (0%)	13 of 30 (43.3%)	0 of 30
Cohort 2 - Gefapixant 50 mg	1 of 30 (3.3%)	9 of 30 (30%)	0 of 30
Cohort 2- Placebo	0 of 29 (0%)	2 of 29 (6.9%)	0 of 29

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publicationLATE-BREAKING ABSTRACT: Tackling the burden of chronic cough: A dose escalation study of AF-219 Jaclyn Smith, Michael Kitt, Mandel Sher, Peter Butera, Anthony Ford European Respiratory Journal 2016 48: OA1976; DOI: 10.1183/13993003.congress-2016.OA1976
Results publication: PubMed 31949115Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, Holt K, Sen S, Sher MR, Ford AP. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020 Mar 20;55(3):1901615. doi: 10.1183/13993003.01615-2019. Print 2020 Mar.
P2X3 Receptor Antagonist (AF-219) in Refractory Chronic Cough: A Randomised, Double-Blind, Placebo-Controlled Phase 2 StudyLink provided by the sponsor.
Individual participant dataSharing planned: Yes. https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Gefapixant in people with Refractory Chronic Cough, run by Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1 (time frame: Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02349425, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2020.