A Study of Gefapixant (MK-7264) in Adult Participants With Chronic Cough (MK-7264-027)

• ClinicalTrials.gov Identifier: NCT03449134
• Recruitment Status: Completed
• First Posted: February 28, 2018
• Results First Posted: June 16, 2021
• Last Update Posted: June 16, 2021
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: February 22, 2018
• First Posted Date: February 28, 2018
• Results First Submitted Date: May 7, 2021
• Results First Posted Date: June 16, 2021
• Last Update Posted Date: June 16, 2021
• Actual Study Start Date: March 14, 2018
• Actual Primary Completion Date: June 5, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2021)

• Model-Based Geometric Mean Ratio (GMR) of 24-hour Objective Coughs Per Hour (Week 12/Baseline) [ Time Frame: Baseline, Week 12 ]
  24-hour objective coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) divided by 24 hours (denominator could be different if the recording period was actually <24 hours but ≥20 hours). Assessment was based on 24-hour sound recordings using a digital recording device which recorded sounds from the lungs and trachea through a chest contact sensor, as well as ambient sounds through a lapel microphone. A longitudinal analysis of covariance (ANCOVA) model was applied to log-transformed cough counts to determine geometric mean (GM) 24-hour objective coughs per hour at baseline and Week 12 on the original scale. The GMR corresponding to the Week 12 GM 24-hour objective coughs per hour divided by the Baseline GM 24-hour objective coughs per hour was reported for all treatment study arms.
• Number of Participants Experiencing At Least One Adverse Event (AE) During Treatment and Follow-up [ Time Frame: Up to approximately 54 weeks ]
  An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with at least one AE during either the 52-week treatment period or 2-week telephone follow-up was reported for all treatment study arms.
• Number of Participants Who Discontinued Treatment Due to AEs [ Time Frame: Up to approximately 52 weeks ]
  An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study intervention during the 52-week treatment period due to an AE for which the action taken was listed as 'drug withdrawn' was reported for all treatment study arms.

Original Primary Outcome Measures (submitted: February 22, 2018)

• 24-hour coughs per hour at Week 12 [ Time Frame: 12 weeks ]
  Assessment of 24-hour coughs per hour (average hourly cough frequency based on 24-hour sound recordings), evaluated using a digital recording device which records sounds from the lungs and trachea through a chest contact sensor, as well as ambient sounds through a lapel microphone.
• Percentage of Participants Experiencing At Least One Adverse Event (AE) During Treatment and Follow-up [ Time Frame: 54 weeks ]
  Assessment of participants who had at least one AE during the main study period (12 weeks), the treatment extension period (40 weeks), and during 2 weeks of follow-up by telephone.
• Percentage of Participants Who Discontinued Treatment Due to AEs [ Time Frame: 52 weeks ]
  Assessment of participants who discontinued treatment due to AEs during the main study period (12 weeks) and the treatment extension period (40 weeks).

Current Secondary Outcome Measures (submitted: May 7, 2021)

• Model-Based Geometric Mean Ratio (GMR) of Awake Objective Coughs Per Hour (Week 12/Baseline) [ Time Frame: Baseline, Week 12 ]
  Awake objective coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) while the participant is awake divided by the total duration (in hours) for the monitoring period that the participant was awake. Assessment was based on 24-hour sound recordings using a digital recording device which recorded sounds from the lungs and trachea through a chest contact sensor, as well as ambient sounds through a lapel microphone. A longitudinal ANCOVA model was applied to log-transformed cough counts to determine GM awake objective coughs per hour at baseline and Week 12 on the original scale. The GMR corresponding to the Week 12 GM awake objective coughs per hour divided by the Baseline GM awake objective coughs per hour was reported for all treatment study arms.
• Percentage of Participants (Model-Based) With a ≤ -30% Change From Baseline in 24-hour Objective Coughs Per Hour at Week 12 [ Time Frame: Baseline, Week 12 ]
  24-hour coughs per hour was defined as the total number of cough events during the monitoring period (24-hour interval) divided by 24 hours (denominator could be different if the recording period was actually <24 hours but ≥20 hours). Assessment based on 24-hour sound recordings using a digital recording device. Percent change in 24-hour coughs per hour = (change from baseline in 24-hour coughs per hour / baseline 24-hour coughs per hour) ×100%. Negative values indicate a decrease in cough rate, while positive values indicate an increase in cough rate. A participant was considered a responder if the percent change from baseline in 24-hour coughs per hour was ≤ -30% (or a ≥30% reduction from baseline); a participant was considered a non-responder otherwise. The percentage of participants (logistic regression model-based) with a ≤ -30% change from baseline in 24-hour coughs per hour at Week 12 (≥30% reduction from baseline) was reported for all treatment study arms.
• Percentage of Participants (Model-Based) With a ≤ -1.3-point Change From Baseline in Mean Weekly Cough Severity Diary (CSD) Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  The CSD evaluates frequency of cough, intensity of cough and disruption and has a total of 7 items, each with scores ranging from 0 (best) to 10 (worst). The total daily CSD score was the sum of these seven item scores (Min=0, Max=70). Mean weekly total score was defined as the average of the mean total daily scores collected during the week prior to each visit. Baseline was defined as the average CSD scores collected during the week prior to Day 1 (Day -6 to Day 0). Participants were considered responders if the change from baseline in mean weekly CSD total score was ≤ -1.3 points (or a ≥1.3 point reduction from baseline); and considered a non-responder otherwise. Negative values indicate a decrease in cough severity, while positive values indicate an increase in cough severity. The percentage of participants (logistic regression model-based) with a ≤ -1.3 point change from baseline in CSD at Week 12 (or ≥1.3 point reduction from baseline) was reported for all treatment study arms.
• Percentage of Participants (Model-Based) With a ≤ -2.7-point Change From Baseline in Mean Weekly CSD Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  The CSD evaluates frequency of cough, intensity of cough and disruption and has a total of 7 items, each with scores ranging from 0 (best) to 10 (worst). The total daily CSD score was the sum of these seven item scores (Min=0, Max=70). Mean weekly total score was defined as the average of the mean total daily scores collected during the week prior to each visit. Baseline was defined as the average CSD scores collected during the week prior to Day 1 (Day -6 to Day 0). Participants were considered responders if the change from baseline in mean weekly CSD total score was ≤ -2.7 points (or a ≥2.7 point reduction from baseline); and considered a non-responder otherwise. Negative values indicate a decrease in cough severity, while positive values indicate an increase in cough severity. The percentage of participants (logistic regression model-based) with a ≤ -2.7 point change from baseline in CSD at Week 12 (or ≥2.7 point reduction from baseline) was reported for all treatment study arms.
• Percentage of Participants (Model-Based) With a ≤ -30 Millimeter (mm) Change From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  Cough severity was scored using the Cough Severity VAS, a single-item question asking the participant to rate the severity of their cough "today" using a 100 mm VAS (100-point scale) ranging from 0 ("No Cough") to 100 ("Extremely Severe Cough"). Mean weekly VAS score was derived as the average of VAS scores collected during the week prior to each visit. Baseline was defined as the average VAS scores collected during the week prior to Day 1 (Day -6 to Day 0). A participant was considered a responder if the change from baseline in mean weekly Cough Severity VAS score was ≤-30 mm (or a ≥30 mm reduction from baseline); participants considered non-responders otherwise. Negative values indicate a decrease in cough severity, while positive values indicate an increase in cough severity. The percentage of participants (logistic regression model-based) with ≤ -30 mm change from baseline in Cough Severity VAS at Week 12 (≥30 mm reduction from baseline) was reported for all treatment study arms.
• Percentage of Participants (Model-Based) With a ≥1.3-point Change From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  The LCQ assesses the impact of chronic cough on health-related quality of life. It consists of 19 items which are divided over 3 domains: Physical (items 1, 2, 3, 9, 10, 11, 14 and 15), Psychological (4, 5, 6, 12, 13, 16, and 17), and Social (7, 8, 18, 19). A 7-point Likert scale is used to rate each item. For each domain, the domain score (range 1-7) is the sum of individual item score within the domain divided by the number of items in the domain. LCQ total score is the sum of the three domain scores and ranges from 3-21; with a higher score corresponding to a better health status. A participant was considered a responder if the change from baseline in LCQ total score was ≥1.3-points (increase from baseline); a participant was considered a non-responder otherwise. The percentage of participants (logistic regression model-based) with a ≥1.3-point change from baseline in LCQ total score at Week 12 was reported for all treatment study arms.

Original Secondary Outcome Measures (submitted: February 22, 2018)

• Awake Coughs Per Hour at Week 12 [ Time Frame: Week 12 ]
  Assessment of coughs per hour while the participant is awake, evaluated using a chest contact sensor to record sounds from the lungs and trachea and a lapel microphone to record ambient sounds.
• Percentage of Participants With a >=30% Reduction From Baseline in 24-hour Coughs Per Hour at Week 12 [ Time Frame: Baseline, Week 12 ]
  Assessment of the change from Baseline in 24-hour coughs per hour at Week 12
• Percentage of Participants With a >=1.3-point Reduction From Baseline in Mean Weekly Cough Severity Diary (CSD) Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  Assessment of the change from Baseline in CSD Total mean weekly score at Week 12
• Percentage of Participants With a >=2.7-point Reduction From Baseline in Mean Weekly CSD Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  Assessment of the change from Baseline in CSD Total mean weekly score at Week 12
• Percentage of Participants With a >=30 mm Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  Assessment of the change from Baseline in the Cough Severity VAS score at Week 12. The VAS is a single-item questionnaire with the response on a 100-point scale ranging from 0 ("No Cough") to 100 ("Extremely Severe Cough").
• Percentage of Participants With a >=1.3-point Increase From Baseline in Leicester Cough Questionnaire (LCQ) Total Score at Week 12 [ Time Frame: Baseline, Week 12 ]
  Assessment of the change from Baseline in the LCQ Total score at Week 12. The 19-item LCQ assesses the impact of cough severity on physical, social and psychological functioning.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Gefapixant (MK-7264) in Adult Participants With Chronic Cough (MK-7264-027)
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Month Study to Evaluate the Efficacy and Safety of MK-7264 in Adult Participants With Chronic Cough (PN027)
• Brief Summary: The main objectives of this study will be to evaluate the efficacy of gefapixant in reducing cough frequency as measured over a 24-hour period at Week 12, and to evaluate the safety and tolerability of gefapixant. The primary hypothesis is that at least one gefapixant dose is superior to placebo in reducing coughs per hour (over 24 hours) at Week 12.

Detailed Description

The study will include a screening period to determine participant inclusion, and the Baseline visit will include 24 hours of objective measurement of cough. The study will consist of two treatment periods, a main 12-week treatment period and a 40-week extension period (52 weeks total treatment), followed by a 14-day telephone follow-up period.

Participants at selected sites and countries who complete the main and extension study periods may consent to participate in an observational, 3-month, Off-treatment Durability Study Period, which extends the Estimated Study Completion Date. The Off-treatment Durability Study Period will explore the impact of withdrawing gefapixant in refractory or unexplained chronic cough participants who have been treated for 1 year.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants with refractory or unexplained chronic cough will be randomized to 1 of 3 treatment groups during the Treatment Period: Placebo, gefapixant 15 mg twice daily (BID), or gefapixant 45 mg BID. Participants will remain on their assigned treatment throughout the study. A safety follow-up phone call will be conducted at a minimum of 14 days after last dose of study treatment.

Masking: Double (Participant, Investigator)
Primary Purpose: Treatment

• Condition: Chronic Cough

Intervention

• Drug: Placebo
  Participants receive dose-matched placebo tablets orally BID during the 12-week main study period and during the 40-week extension period.
• Drug: Gefapixant
  Gefapixant 15 mg or 45 mg tablet administered orally BID during the 12-week main study period and during the 40-week extension period, according to randomization.
  Other Name: MK-7264

Study Arms

• Placebo Comparator: Placebo
  Participants receive dose-matched placebo tablets twice daily (BID) during the 12-week main study period and 40-week extension period.
  Intervention: Drug: Placebo
• Experimental: Gefapixant 15 mg BID
  Participants receive a gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg BID during the 12-week main study period and 40-week extension period.
  Interventions:

  • Drug: Placebo
  • Drug: Gefapixant
• Experimental: Gefapixant 45 mg BID
  Participants receive a gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the 12-week main study period and 40-week extension period.
  Interventions:

  • Drug: Placebo
  • Drug: Gefapixant

Publications *

• Dicpinigaitis PV, Birring SS, Blaiss M, McGarvey LP, Morice AH, Pavord ID, Satia I, Smith JA, La Rosa C, Li Q, Nguyen AM, Schelfhout J, Tzontcheva A, Muccino D. Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough. Ann Allergy Asthma Immunol. 2023 Jan;130(1):60-66. doi: 10.1016/j.anai.2022.05.003. Epub 2022 May 13.
• McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, Nguyen AM, Li Q, Tzontcheva A, Iskold B, Green SA, Rosa C, Muccino DR, Smith JA; COUGH-1 and COUGH-2 Investigators. Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022 Mar 5;399(10328):909-923. doi: 10.1016/S0140-6736(21)02348-5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 10, 2020): 732
• Original Estimated Enrollment (submitted: February 22, 2018): 720
• Actual Study Completion Date: August 17, 2020
• Actual Primary Completion Date: June 5, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Chest radiograph or computed tomography scan of the thorax (within 5 years of Screening/Visit 1 and after the onset of chronic cough) not demonstrating any abnormality considered to be significantly contributing to the chronic cough or any other clinically significant lung disease in the opinion of the principal investigator or the sub-investigator
• Has had chronic cough for at least 1 year with a diagnosis of refractory chronic cough or unexplained chronic cough
• Female participants are eligible if not pregnant, not breastfeeding, and either not of childbearing potential, or agree to follow contraceptive guidance
• Provides written informed consent and is willing and able to comply with the study protocol (including use of the digital cough recording device and completion of study questionnaires)

Exclusion Criteria:

• Is a current smoker or has given up smoking within 12 months of Screening
• Has forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) ratio <60%
• Has a history of respiratory tract infection or recent clinically significant change in pulmonary status
• Has a history of chronic bronchitis
• Is currently taking an angiotensin converting enzyme inhibitor (ACEI), or has used an ACEI within 3 months of Screening
• Has an estimated glomerular filtration rate (eGFR) <30mL/min/1.73 m^2 at Screening OR eGFR ≥30 mL/min/1.73 m^2 and <50 mL/min/1.73 m^2 at Screening with unstable renal function
• Has a history of malignancy <=5 years
• Is a user of recreational or illicit drugs or has had a recent history of drug or alcohol abuse or dependence
• Has a history of anaphylaxis or cutaneous adverse drug reaction (with or without systemic symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs
• Has systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm Hg at Screening
• Has a known allergy/sensitivity or contraindication to gefapixant
• Has donated or lost >=1 unit of blood within 8 weeks prior to the first dose of gefapixant
• Has previously received gefapixant or is currently participating in or has participated in an interventional clinical study
• Had significantly abnormal laboratory tests at Screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Canada, Czechia, Denmark, France, Hungary, Israel, Japan, Korea, Republic of, Peru, Poland, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03449134
• Other Study ID Numbers: 7264-027; MK-7264-027 ( Other Identifier: Merck Protocol Number ); 2017-000537-31 ( EudraCT Number ); 184098 ( Registry Identifier: JAPAN-CTI )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: June 2021