A Study of Gefapixant (AF-219/MK-7264) in Participants With Idiopathic Pulmonary Fibrosis (IPF) With Persistent Cough (MK-7264-016)

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled, crossover, dose escalation study of gefapixant (AF-219) in participants with Idiopathic Pulmonary Fibrosis (IPF) with persistent cough.

Detailed Description
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Prior to Amendment 3, participants were randomized to receive either placebo twice daily (BID) for 14 days during Period 1 followed by gefapixant 50 mg BID for 10 days then gefapixant 150 mg BID for 4 days BID during Period 2; or gefapixant 50 mg BID for 10 days then gefapixant 150 mg BID for 4 days during Period 1, followed by placebo BID for 14 days during Period 2. Each period was separated by a 14 to 21-day washout period. During Amendment 3, participants were randomized to receive either placebo BID for 14 days during Period 1 followed by gefapixant 50 mg BID for 14 days during Period 2; or gefapixant 50 mg BID for 14 days during Period 1, followed by placebo BID for 14 days during Period 2. Each period was separated by a 14 to 21-day washout period.

Official Title
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A Randomized Placebo-Controlled Study to Assess the Efficacy and Safety of AF-219, a P2X3 Receptor Antagonist, in Subjects With Idiopathic Pulmonary Fibrosis (IPF) With Persistent Cough

Conditions
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Idiopathic Pulmonary Fibrosis, Cough

Intervention / Treatment
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* Drug: Gefapixant
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic pulmonary fibrosis diagnosis based upon the American Thoracic Society (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/ Latin American Thoracic Society (ALAT) IPF 2011 guideline Life expectancy of greater than 6 months Stable medical condition (IPF) for at least 4 weeks Self-reported history of troublesome daily cough for more than 8 weeks Score of ≥ 40mm on the Cough Severity Visual Analogue 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 subjects 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 (i.e., within the last 30 days). Initiation of treatment with an ACE-inhibitor within 4 weeks prior to the Baseline Visit (Day 0) or during the study History of upper and/or lower respiratory tract infection within 4 weeks of the Baseline Visit (Day 0) History of opioid use for treatment of cough within 1 week of the Baseline Visit (Day 0) Requiring prohibited medications Body mass index (BMI) <18 kg/m^2 or ≥ 40 kg/m^2 History or symptoms of renal disease or renal obstructive disease 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 Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection) Recent history of stroke or transient ischemic attack (within 6 months prior to Screening) not due to trauma, repaired vascular malformation, or aneurysm Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood pressure (DBP) >90 mm Hg QTc interval >450 milliseconds in males, >470 milliseconds in females Significantly abnormal laboratory tests at Screening Breastfeeding Treatment with an investigational drug or biologic within 30 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: 40 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: Gefapixant>Placebo Pre-Amendment 3<br>Gefapixant 50 mg twice daily (BID) for 10 days, then 150 mg BID for 4 days in Period 1, followed by a 14-21 day washout period, then placebo BID for 14 days in Period 2 | Drug: Gefapixant<br>* Gefapixant 50 mg tablet, administered by mouth<br>* Other names: MK-7264;Other: Placebo<br>* Matching placebo to gefapixant, tablet administered by mouth<br>|
| Experimental: Placebo>Gefapixant Pre-Amendment 3<br>Placebo BID for 14 days in Period 1, followed by a 14-21 day washout period, then gefapixant 50 mg BID for 10 days, then 150 mg for 4 days in Period 2 | Drug: Gefapixant<br>* Gefapixant 50 mg tablet, administered by mouth<br>* Other names: MK-7264;Other: Placebo<br>* Matching placebo to gefapixant, tablet administered by mouth<br>|
| Experimental: Gefapixant>Placebo Post-Amendment 3<br>Gefapixant 50 mg twice daily (BID) for 14 days in Period 1, followed by a 14-21 day washout period, then placebo BID for 14 days in Period 2 | Drug: Gefapixant<br>* Gefapixant 50 mg tablet, administered by mouth<br>* Other names: MK-7264;Other: Placebo<br>* Matching placebo to gefapixant, tablet administered by mouth<br>|
| Experimental: Placebo>Gefapixant Post-Amendment 3<br>Placebo BID for 14 days in Period 1, followed by a 14-21 day washout period, then gefapixant 50 mg BID for 14 days in Period 2 | Drug: Gefapixant<br>* Gefapixant 50 mg tablet, administered by mouth<br>* Other names: MK-7264;Other: Placebo<br>* Matching placebo to gefapixant, tablet administered by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mixed Model of Repeated Measures (MMRM) Change From Baseline in Awake Objective Cough Frequency (Periods 1 & 2 Combined) | Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was analyzed using Mixed Effect Model for Repeated Measures (MMRM) to evaluate the results of the 2-period cross-over study. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. A negative change indicates a decrease in cough frequency, while a positive change indicates an increase in cough frequency. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Awake Objective Cough Frequency (Periods 1 & 2 Combined) | Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined) | Cough monitoring was conducted for 24 hours while awake, at pre-dose on Day 0 (baseline), and after administration of the study drug on Day 7 and Day 14 in Periods 1 and 2. The cough frequency is the coughs/hour over each 24-hour period. Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. A negative value indicates a decrease in cough frequency. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Percent Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined) | Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Percent change from baseline in awake objective cough frequency (0-6 hours after the morning dose) was reported at each dosing interval. Percent change in awake cough frequency = 100 X (post treatment cough frequency - baseline cough frequency) divided by the baseline cough frequency. A negative value indicates a decrease in cough frequency. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 1) | Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Change from Baseline in awake cough frequency = post-treatment awake cough frequency - Baseline awake cough frequency. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the end of the dosing period. Awake objective cough frequency for Period 1 was analyzed for using MMRM to evaluate the results of the 2-period cross-over study. The derived change measured at each dose were the repeated measures. | Baseline (Day 0), Day 7, and Day 14 (Period 1) | 
| MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 2) | Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. Change from baseline in awake cough frequency = post-treatment awake cough frequency - Baseline awake cough frequency. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period while the post-treatment cough frequency was derived from the cough monitoring performed at the at the end of the dosing period. Awake objective cough frequency for Period 2 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. | Baseline (Day 0), Day 7, and Day 14 (Period 2) | 
| Responder Analysis of Awake Cough Frequency at Day 7 (Periods 1 & 2 Combined) | Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. The number of participants that met responder criteria for ≥70%, ≥50%, ≥30%, and ≥20% change (reduction) from baseline levels in 24-hour awake cough frequency was reported (Period 1 and Period 2 combined) at Day 7. | Day 7 (Period 1 and Period 2) | 
| Responder Analysis of Awake Cough Frequency at Day 14 (Periods 1 & 2 Combined) | Awake objective cough frequency was defined as the total number of cough events during the monitoring period the participant was awake divided by the total duration for the monitoring period the participant was awake. The number of participants that met responder criteria for ≥70%, ≥50%, ≥30%, and ≥20% change (reduction) from baseline levels in 24-hour awake cough frequency was reported (Period 1 and Period 2 combined) at Day 14. | Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. 24-hour objective 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 1) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. 24-hour objective cough frequency for Period 1 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1) | 
| MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 2) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. 24-hour objective cough frequency for Period 2 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. | Baseline (Day 0), Day 7, and Day 14 (Period 2) | 
| 24-hour Objective Cough Frequency (Periods 1 & 2 Combined) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. 24-hour objective 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Percent Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined) | 24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Percent change in cough frequency = 100 X (post treatment cough frequency - baseline cough frequency) divided by the baseline cough frequency. A negative value indicates a decrease in cough frequency. A positive value indicates an increase in cough frequency. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in Sleep Cough Frequency (Periods 1 & 2 Combined) | Sleep 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 recordings were collected with a digital recording device. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. Sleep 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in Cough Visual Analog Scale (VAS) (Periods 1 & 2 Combined) | 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. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency. 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in Cough Quality of Life Questionnaire (CQLQ) (Periods 1 & 2 Combined) | CQLQ is a 28-item scale that has 4 possible responses: 1 = strongly disagree; 2 = disagree; 3 = agree; 4 = strongly agree. Subjects were instructed to circle only 1 response. The total CQLQ score is the sum of the individual item scores; the lowest possible score is 28 and the highest 112. Low CQLQ scores for both total and the 6 domains indicate less impact of cough on health-related quality of life. A negative result indicates a decrease in cough impact on quality of life. CQLQ 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in Total Daily Cough Severity Diary (CSD) Score (Periods 1 & 2 Combined) | 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. 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. | Baseline (Day 0), Week 1, and Week 2 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (Periods 1 & 2 Combined) | UCSD SOBQ is a 24-point item scale to assess shortness of breath questionnaire that has a 6-point scale ranging from 0 to 5 (0 = not at all, to 5 = maximal or unable to do because of breathlessness. Lowest possible score is 0 and the highest possible score is 120. The higher the score the more out of breath the participant is reporting. A negative value indicates less breathlessness. UCSD SOBQ 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| MMRM Analysis of Change From Baseline in Cough Borg CR10 Scale Score (Periods 1 & 2 Combined) | The Borg 10 scale assesses post-treatment breathlessness during perceived exertion while exercising. The scale ranges from 0 to 10 where 0 = nothing at all, 1 = very weak, 3 = moderate, 5 = strong, 7 = very strong, 10 = extremely strong. The lowest possible score is 0 and the highest possible score is 10. A negative value indicates less breathlessness. Cough Borg CR10 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. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Percentage of Participants With Borg CR10 Perception of Breathless Value ≥5 (Periods 1 & 2 Combined) | The Borg 10 scale assesses post-treatment breathlessness during perceived exertion while exercising. The scale ranges from 0 to 10 where 0 = nothing at all, 1 = very weak, 3 = moderate, 5 = strong, 7 = very strong, 10 = extremely strong. The lowest possible score is 0 and the highest possible score is 10. The percentage of participants with Borg CR10 perception of breathless value ≥5 was assessed. | Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2) | 
| Patient's Global Impression of Change (PGIC) Day 7 (Periods 1 & 2 Combined) | PGIC is the participant self-reported overall improvement of cough following administration of study drug. The PGIC has a 7-point rating scale of very much improved, much improved, 'minimally improved, no change, minimally worse, much worse and very much worse. | Day 7 (Period 1 and Period 2) | 
| Patient's Global Impression of Change (PGIC) Day 15 (Periods 1 & 2 Combined) | PGIC is the participant self-reported overall improvement of cough following administration of study drug. The PGIC has a 7-point rating scale of very much improved, much improved, 'minimally improved, no change, minimally worse, much worse and very much worse. | Day 15 (Period 1 and Period 2) | 
| Clinician's Global Impression of Change (CGIC) Day 15 (Periods 1 & 2 Combined) | CGIC is the clinician's-reported overall improvement of participant's cough following administration of study drug. The CGIC has a 7-point rating scale of very much improved, much improved, 'minimally improved, no change, minimally worse, much worse and very much worse. | Day 15 (Period 1 and Period 2) | 
| Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least Six Months | At the end of the treatment period, participants were asked How likely would you be to take this medication for at least 6 months? The degree of taste acceptability was measured on a scale of extremely unlikely, unlikely, neither, likely and extremely likely. | After last treatment, up to Day 15 (Period 1 and Period 2) | 
| Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least One Year | At the end of the treatment period, the participant was asked How likely would you be to take this medication for at least one year? The degree of taste acceptability was measured on a scale of extremely unlikely, unlikely, neither, likely and extremely likely. | After last treatment, up to Day 15 (Period 1 and Period 2) |