Chronic Cough
Conditions
Brief summary
The primary objective of this study will be to evaluate the efficacy of gefapixant (MK-7264) in reducing cough frequency as measured over a 24-hour period. It is hypothesized that at least one dose of gefapixant is superior to placebo in reducing coughs per hour (over 24 hours) at Week 24.
Detailed description
This study will have a main 24-week treatment period and a 28-week extension period of treatment. 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.
Interventions
DRUGGefapixant 45 mg twice daily (BID)
Gefapixant 45 mg tablet to be administered orally BID
Gefapixant 15 mg tablet to be administered orally BID
DRUGPlacebo
Placebo tablet administered orally BID
Gefapixant 45 mg tablet to be administered orally BID
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Participants with refractory or unexplained chronic cough will be randomized to 1 of 3 treatment groups: gefapixant 45 mg twice daily (BID), gefapixant 15 mg BID, or placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Is a female who is not pregnant, not breastfeeding, not of childbearing potential, or agrees 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, or is a former smoker with greater than 20 pack-years * 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) \<30 mL/min/1.73 m\^2 at Screening OR an 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Model-Based Geometric Mean Ratio (GMR) of 24-Hour Coughs Per Hour at Week 24 | Baseline, Week 24 | 24-hour coughs per hour was defined as the average hourly cough frequency based on 24-hour sound recordings using a digital recording device (cough monitor). A longitudinal analysis of covariance (ANCOVA) model was applied to log-transformed cough data to determine geometric mean (GM) 24-hour coughs per hour at baseline and week 24. The GMR (Week 24 GM 24-hour coughs per hour divided by Baseline GM 24-hour coughs per hour) is reported. |
| Percentage of Participants Who Experienced At Least One Adverse Event (AE) During Treatment and Follow-up | Up to 54 weeks | Assessment of participants who have at least one AE during the main study period (24 weeks), the treatment extension period (28 weeks), and during 2 weeks of follow-up by telephone. |
| Percentage of Participants Who Discontinued Treatment Due to an AE | Up 52 weeks | Assessment of participants who stop study treatment due to an AE during the main study period (24 weeks) or the treatment extension period (28 weeks). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥1.3-point Reduction From Baseline of Mean Weekly Cough Severity Diary (CSD) Total Score at Week 24 | Baseline, Week 24 | The 7-item CSD was used to record participants' daily cough frequency, cough intensity, and disruption due to cough. Each item was rated on an 11-point scale 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 CSD total score was defined as the average of the mean total daily scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥1.3 point reduction from baseline in CSD at Week 24 is reported. |
| Model-Based GMR of Awake Coughs Per Hour at Week 24/Baseline | Baseline, Week 24 | Awake coughs per hour was defined as the average hourly cough frequency while the participant is awake, based on a 24-hour interval of sound recordings using a digital recording device (cough monitor). ANCOVA model was applied to log-transformed cough data to determine GM of awake coughs per hour at baseline and week 24. The GMR (Week 24 GM awake coughs per hour divided by Baseline GM awake coughs per hour) is reported. |
| Percentage of Participants With a ≥30 mm Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 24 | Baseline, Week 24 | 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). Mean weekly VAS score was defined as the average of the VAS scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥30mm reduction from baseline in cough severity VAS score at Week 24 is reported. |
| Percentage of Participants With ≥2.7-point Reduction From Baseline of Mean Weekly CSD Total Score at Week 24 | Baseline, Week 24 | The 7-item CSD was used to record participants' daily cough frequency, cough intensity, and disruption due to cough. Each item was rated on an 11-point scale 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 CSD total score was defined as the average of the mean total daily scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥2.7 point reduction from baseline in CSD at Week 24 is reported. |
| Percentage of Participants With a ≥1.3-point Increase From Baseline in the Leicester Questionnaire (LCQ) Total Score at Week 24 | Baseline, Week 24 | The 19-item LCQ assessed the impact of chronic cough in three health-related quality of life (HRQoL) domains (physical, social and psychological). The LCQ is calculated as a mean score for each domain ranging from 1 to 7, with a total score ranging from 3 to 21. Higher scores indicate better HRQoL. A clinically meaningful improvement from baseline in HRQoL was defined as ≥1.3-point increase in the LCQ total score at Week 24. The percentage of participants (logistic regression model-based) with a ≥1.3-point increase in the LCQ total score at Week 24 is presented. |
| Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Coughs Per Hour at Week 24 | Baseline, Week 24 | 24-hour coughs per hour was defined as the average hourly cough frequency based on 24-hour sound recordings using a digital recording device (cough monitor). A clinically meaningful improvement from baseline is defined as a ≥30% reduction in 24-hour coughs per hour at week 24. The percentage of participants (logistic regression model-based) with a ≥30% reduction from baseline in 24-hour coughs per hour at Week 24 (≥30% reduction from baseline) is presented. |
Countries
China
Participant flow
Recruitment details
The China extension study enrolled 161 participants. Of the 161 total participants, 4 were previously enrolled in the global study for MK-7264-030 (NCT03449147). Randomization to the gefapixant 15 mg twice daily (BID) was discontinued during the China enrollment period per protocol amendment 5.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received dose-matched placebo tablets twice daily (BID) during the 24-week main study period and 28-week extension period. | 67 |
| Gefapixant 15 mg BID Participants received a gefapixant 15 mg tablet BID during the main study period (24 weeks) and also during the extension period (28 weeks). This arm was not included in protocol amendment 5 or later. | 27 |
| Gefapixant 45 mg Twice Daily (BID) Participants received a gefapixant 45 mg tablet BID during the 24-week main study period and 28-week extension period. | 66 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Screen Failure | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 14 | 6 | 20 |
Baseline characteristics
| Characteristic | Placebo | Gefapixant 15 mg BID | Gefapixant 45 mg Twice Daily (BID) | Total |
|---|---|---|---|---|
| Age, Continuous | 44.2 Years STANDARD_DEVIATION 15.1 | 44.8 Years STANDARD_DEVIATION 12.7 | 48.0 Years STANDARD_DEVIATION 14.5 | 45.9 Years STANDARD_DEVIATION 14.5 |
| Baseline 24-Hour Coughs Per Hour | 29.65 Coughs/hour STANDARD_DEVIATION 53.24 | 40.28 Coughs/hour STANDARD_DEVIATION 66.66 | 38.62 Coughs/hour STANDARD_DEVIATION 49.33 | 35.19 Coughs/hour STANDARD_DEVIATION 54.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 27 Participants | 66 Participants | 160 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 67 Participants | 27 Participants | 66 Participants | 160 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 32 Participants | 11 Participants | 32 Participants | 75 Participants |
| Sex: Female, Male Male | 35 Participants | 16 Participants | 34 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 27 | 0 / 66 |
| other Total, other adverse events | 42 / 67 | 17 / 27 | 53 / 66 |
| serious Total, serious adverse events | 4 / 67 | 4 / 27 | 2 / 66 |
Outcome results
Primary
Model-Based Geometric Mean Ratio (GMR) of 24-Hour Coughs Per Hour at Week 24
24-hour coughs per hour was defined as the average hourly cough frequency based on 24-hour sound recordings using a digital recording device (cough monitor). A longitudinal analysis of covariance (ANCOVA) model was applied to log-transformed cough data to determine geometric mean (GM) 24-hour coughs per hour at baseline and week 24. The GMR (Week 24 GM 24-hour coughs per hour divided by Baseline GM 24-hour coughs per hour) is reported.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Participants needed to have baseline and at least 1 post-baseline measurement. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Model-Based Geometric Mean Ratio (GMR) of 24-Hour Coughs Per Hour at Week 24 | 0.47 Ratio |
| Gefapixant 45 mg Twice Daily (BID) | Model-Based Geometric Mean Ratio (GMR) of 24-Hour Coughs Per Hour at Week 24 | 0.51 Ratio |
p-value: 0.71395% CI: [-30.51, 70.03]ANCOVA
Primary
Percentage of Participants Who Discontinued Treatment Due to an AE
Assessment of participants who stop study treatment due to an AE during the main study period (24 weeks) or the treatment extension period (28 weeks).
Time frame: Up 52 weeks
Population: All randomized China participants who received at least 1 dose of study intervention. Participants were analyzed in the group as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Percentage of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants Who Discontinued Treatment Due to an AE | 1 Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants Who Discontinued Treatment Due to an AE | 5 Participants |
Primary
Percentage of Participants Who Experienced At Least One Adverse Event (AE) During Treatment and Follow-up
Assessment of participants who have at least one AE during the main study period (24 weeks), the treatment extension period (28 weeks), and during 2 weeks of follow-up by telephone.
Time frame: Up to 54 weeks
Population: All randomized China participants who received at least 1 dose of study intervention. Participants were analyzed in the group as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Percentage of Participants Who Experienced At Least One Adverse Event (AE) During Treatment and Follow-up | 54 Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants Who Experienced At Least One Adverse Event (AE) During Treatment and Follow-up | 20 Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants Who Experienced At Least One Adverse Event (AE) During Treatment and Follow-up | 58 Participants |
Secondary
Model-Based GMR of Awake Coughs Per Hour at Week 24/Baseline
Awake coughs per hour was defined as the average hourly cough frequency while the participant is awake, based on a 24-hour interval of sound recordings using a digital recording device (cough monitor). ANCOVA model was applied to log-transformed cough data to determine GM of awake coughs per hour at baseline and week 24. The GMR (Week 24 GM awake coughs per hour divided by Baseline GM awake coughs per hour) is reported.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have awake 24-hour cough data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Model-Based GMR of Awake Coughs Per Hour at Week 24/Baseline | 0.46 Ratio |
| Gefapixant 45 mg Twice Daily (BID) | Model-Based GMR of Awake Coughs Per Hour at Week 24/Baseline | 0.51 Ratio |
p-value: 0.62895% CI: [-28.68, 74.57]ANCOVA
Secondary
Percentage of Participants With ≥1.3-point Reduction From Baseline of Mean Weekly Cough Severity Diary (CSD) Total Score at Week 24
The 7-item CSD was used to record participants' daily cough frequency, cough intensity, and disruption due to cough. Each item was rated on an 11-point scale 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 CSD total score was defined as the average of the mean total daily scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥1.3 point reduction from baseline in CSD at Week 24 is reported.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have CSD data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With ≥1.3-point Reduction From Baseline of Mean Weekly Cough Severity Diary (CSD) Total Score at Week 24 | 58.7 Percentage of Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants With ≥1.3-point Reduction From Baseline of Mean Weekly Cough Severity Diary (CSD) Total Score at Week 24 | 61.1 Percentage of Participants |
Comparison: Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, baseline mean weekly CSD total score and the interaction of baseline mean weekly CSD total score by visit as covariates.95% CI: [0.49, 2.49]
Secondary
Percentage of Participants With ≥2.7-point Reduction From Baseline of Mean Weekly CSD Total Score at Week 24
The 7-item CSD was used to record participants' daily cough frequency, cough intensity, and disruption due to cough. Each item was rated on an 11-point scale 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 CSD total score was defined as the average of the mean total daily scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥2.7 point reduction from baseline in CSD at Week 24 is reported.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have CSD data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With ≥2.7-point Reduction From Baseline of Mean Weekly CSD Total Score at Week 24 | 23.9 Percentage of Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants With ≥2.7-point Reduction From Baseline of Mean Weekly CSD Total Score at Week 24 | 37.8 Percentage of Participants |
Comparison: Comparison based on a logistic regression model that included treatment, visit, treatment-by-visit interaction, gender, baseline mean weekly CSD total score, and the interaction of baseline mean weekly CSD total score by visit as covariates95% CI: [0.8, 4.64]
Secondary
Percentage of Participants With a ≥1.3-point Increase From Baseline in the Leicester Questionnaire (LCQ) Total Score at Week 24
The 19-item LCQ assessed the impact of chronic cough in three health-related quality of life (HRQoL) domains (physical, social and psychological). The LCQ is calculated as a mean score for each domain ranging from 1 to 7, with a total score ranging from 3 to 21. Higher scores indicate better HRQoL. A clinically meaningful improvement from baseline in HRQoL was defined as ≥1.3-point increase in the LCQ total score at Week 24. The percentage of participants (logistic regression model-based) with a ≥1.3-point increase in the LCQ total score at Week 24 is presented.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have LCQ data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a ≥1.3-point Increase From Baseline in the Leicester Questionnaire (LCQ) Total Score at Week 24 | 68.4 Percentage of Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants With a ≥1.3-point Increase From Baseline in the Leicester Questionnaire (LCQ) Total Score at Week 24 | 67.5 Percentage of Participants |
p-value: 0.91795% CI: [0.43, 2.13]Regression, Logistic
Secondary
Percentage of Participants With a ≥30 mm Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 24
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). Mean weekly VAS score was defined as the average of the VAS scores collected during the week prior to each visit. The percentage of participants (logistic regression model-based) with a ≥30mm reduction from baseline in cough severity VAS score at Week 24 is reported.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have CSD data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a ≥30 mm Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 24 | 23.0 Percentage of Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants With a ≥30 mm Reduction From Baseline in Cough Severity Visual Analog Scale (VAS) Score at Week 24 | 24.9 Percentage of Participants |
95% CI: [0.45, 2.72]
Secondary
Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Coughs Per Hour at Week 24
24-hour coughs per hour was defined as the average hourly cough frequency based on 24-hour sound recordings using a digital recording device (cough monitor). A clinically meaningful improvement from baseline is defined as a ≥30% reduction in 24-hour coughs per hour at week 24. The percentage of participants (logistic regression model-based) with a ≥30% reduction from baseline in 24-hour coughs per hour at Week 24 (≥30% reduction from baseline) is presented.
Time frame: Baseline, Week 24
Population: All China participants randomized to the gefapixant 45 mg BID or placebo groups who received at least 1 dose of study intervention. Efficacy evaluation of the gefapixant 15 mg BID group was removed from the study objectives of the China cohort per protocol amendment 5. Participants needed to have 24-hour cough data at baseline and at least 1 post-baseline measurement. Participants were analyzed in the group as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Coughs Per Hour at Week 24 | 54.6 Percentage of Participants |
| Gefapixant 45 mg Twice Daily (BID) | Percentage of Participants With a ≥30% Reduction From Baseline in 24-hour Coughs Per Hour at Week 24 | 50.6 Percentage of Participants |
p-value: 0.68795% CI: [0.38, 1.88]Regression, Logistic