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

Study Overview
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Brief Summary
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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.

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

Conditions
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Refractory Chronic Cough

Intervention / Treatment
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* Drug: Gefapixant
* Drug: Placebo (for gefapixant)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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 (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) 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

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Gefapixant>Placebo<br>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. | Drug: Gefapixant<br>* Gefapixant 7.5 and 50mg tablets administered orally<br>* Other names: MK-7264;Drug: Placebo (for gefapixant)<br>* Placebo to gefapixant 7.5 and 50mg tablets administered orally<br>|
| Experimental: Cohort 1: Placebo>Gefapixant<br>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. | Drug: Gefapixant<br>* Gefapixant 7.5 and 50mg tablets administered orally<br>* Other names: MK-7264;Drug: Placebo (for gefapixant)<br>* Placebo to gefapixant 7.5 and 50mg tablets administered orally<br>|
| Experimental: Cohort 2: Gefapixant>Placebo<br>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. | Drug: Gefapixant<br>* Gefapixant 7.5 and 50mg tablets administered orally<br>* Other names: MK-7264;Drug: Placebo (for gefapixant)<br>* Placebo to gefapixant 7.5 and 50mg tablets administered orally<br>|
| Experimental: Cohort 2: Placebo>Gefapixant<br>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. | Drug: Gefapixant<br>* Gefapixant 7.5 and 50mg tablets administered orally<br>* Other names: MK-7264;Drug: Placebo (for gefapixant)<br>* Placebo to gefapixant 7.5 and 50mg tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |