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

• Sponsor: Afferent Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02502097
• Collaborator: (none)
• Enrollment: 51
• Arms: 4
• Actual Duration (Months): 10.6

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis; Cough	Drug: Gefapixant; Other: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Aug 26, 2015
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 14, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gefapixant>Placebo Pre-Amendment 3 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; Gefapixant 50 mg tablet, administered by mouth; Other Names: AF-219 MK-7264 ; Other: Placebo; Matching placebo to gefapixant, tablet administered by mouth
Experimental: Placebo>Gefapixant Pre-Amendment 3 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; Gefapixant 50 mg tablet, administered by mouth; Other Names: AF-219 MK-7264 ; Other: Placebo; Matching placebo to gefapixant, tablet administered by mouth
Experimental: Gefapixant>Placebo Post-Amendment 3 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; Gefapixant 50 mg tablet, administered by mouth; Other Names: AF-219 MK-7264 ; Other: Placebo; Matching placebo to gefapixant, tablet administered by mouth
Experimental: Placebo>Gefapixant Post-Amendment 3 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; Gefapixant 50 mg tablet, administered by mouth; Other Names: AF-219 MK-7264 ; Other: Placebo; Matching placebo to gefapixant, tablet administered by mouth

Outcome Measures

Primary Outcome Measures

1. Mixed Model of Repeated Measures (MMRM) Change From Baseline in Awake Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

   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.

2. Awake Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

   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.

3. Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

   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.

4. Percent Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and 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. 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.

Secondary Outcome Measures

1. MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 1) [Baseline (Day 0), Day 7, and Day 14 (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.

2. MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 2) [Baseline (Day 0), Day 7, and Day 14 (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.

3. Responder Analysis of Awake Cough Frequency at Day 7 (Periods 1 & 2 Combined) [Day 7 (Period 1 and 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. 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.

4. Responder Analysis of Awake Cough Frequency at Day 14 (Periods 1 & 2 Combined) [Day 14 (Period 1 and 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. 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.

5. MMRM Analysis of Change From Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and 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 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.

6. MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 1) [Baseline (Day 0), Day 7, and Day 14 (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.

7. MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 2) [Baseline (Day 0), Day 7, and Day 14 (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.

8. 24-hour Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

   24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period.

9. Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and 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 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.

10. Percent Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

11. MMRM Analysis of Change From Baseline in Sleep Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

12. MMRM Analysis of Change From Baseline in Cough Visual Analog Scale (VAS) (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 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. 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.

13. MMRM Analysis of Change From Baseline in Cough Quality of Life Questionnaire (CQLQ) (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

14. MMRM Analysis of Change From Baseline in Total Daily Cough Severity Diary (CSD) Score (Periods 1 & 2 Combined) [Baseline (Day 0), Week 1, and Week 2 (Period 1 and Period 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. 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.

15. MMRM Analysis of Change From Baseline in University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

16. MMRM Analysis of Change From Baseline in Cough Borg CR10 Scale Score (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

17. Percentage of Participants With Borg CR10 Perception of Breathless Value ≥5 (Periods 1 & 2 Combined) [Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)]

    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.

18. Patient's Global Impression of Change (PGIC) Day 7 (Periods 1 & 2 Combined) [Day 7 (Period 1 and Period 2)]

    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".

19. Patient's Global Impression of Change (PGIC) Day 15 (Periods 1 & 2 Combined) [Day 15 (Period 1 and Period 2)]

    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".

20. Clinician's Global Impression of Change (CGIC) Day 15 (Periods 1 & 2 Combined) [Day 15 (Period 1 and Period 2)]

    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".

21. Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least Six Months [After last treatment, up to Day 15 (Period 1 and Period 2)]

    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."

22. Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least One Year [After last treatment, up to Day 15 (Period 1 and Period 2)]

    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."

Other Outcome Measures

1. Pre-dose Baseline of Awake Objective Cough Frequency [Baseline (Day 0) (Period 1 and 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. Baseline cough frequency was derived from the cough monitoring performed at the beginning of each treatment period.

2. Pre-dose Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 2)]

   24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour cough frequency in Periods 1 and 2 was evaluated based on the participant's randomized group (gefapixant or placebo).

3. Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 1) [Baseline (Day 0) (Period 1)]

   24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour cough frequency for Period 1 was evaluated based on the participant's randomized group (gefapixant or placebo).

4. Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 2) [Baseline (Day 0) (Period 2)]

   24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour objective cough frequency for Period 2 was evaluated based on the participant's randomized group (gefapixant or placebo).

5. Pre-dose Baseline Sleep Cough Frequency [Baseline (Day 0)]

   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. Baseline sleep cough frequency was evaluated based on the participant's randomized group (gefapixant or placebo).

6. Pre-dose Baseline Cough VAS (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 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 was defined as average of screening and baseline cough VAS.

7. Pre-dose Baseline Cough CQLQ (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 2)]

   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. Baseline cough CQLQ was evaluated based on the participant's randomized group (gefapixant or placebo).

8. Pre-dose Baseline Cough Severity CSD (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 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.

9. Pre-dose Baseline of UCSD SOBQ (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 2)]

   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. Baseline of UCSD SOBQ was evaluated based on the participant's randomized group (gefapixant or placebo).

10. Pre-dose Baseline of Cough Borg CR10 Scale Score (Periods 1 & 2 Combined) [Baseline (Day 0) (Period 1 and Period 2)]

    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 baseline of cough Borg CR10 was evaluated based on the participant's randomized group (gefapixant or placebo).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Afferent Pharmaceuticals, Inc.

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Afferent Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02502097
• Other Study ID Numbers: 7264-016; AF-219-016; MK-7264-016
• First Posted: Jul 20, 2015
• Last Update Posted: May 26, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pulmonary Fibrosis; Cough; Idiopathic Pulmonary Fibrosis; Fibrosis

Study Results

Participant Flow

Arm/Group Title	Gefapixant>Placebo Pre-Amendment 3	Placebo>Gefapixant Pre-Amendment 3	Gefapixant>Placebo Post-Amendment 3	Placebo>Gefapixant Post-Amendment 3
Arm/Group Description	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	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	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	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
Period Title: Period 1
STARTED	4	3	22	22
COMPLETED	4	3	21	22
NOT COMPLETED	0	0	1	0
Period Title: Period 1
STARTED	4	3	21	22
COMPLETED	4	2	20	21
NOT COMPLETED	0	1	1	1
Period Title: Period 1
STARTED	4	2	20	21
COMPLETED	4	2	19	21
NOT COMPLETED	0	0	1	0

Baseline Characteristics

Arm/Group Title	Gefapixant>Placebo Pre-Amendment 3	Placebo>Gefapixant Pre-Amendment 3	Gefapixant>Placebo Post-Amendment 3	Placebo>Gefapixant Post-Amendment 3	Total
Arm/Group Description	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	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	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	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	Total of all reporting groups
Overall Participants	4	3	22	22	51
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.0 (5.35)	66.7 (0.53)	69.0 (9.43)	70.0 (5.06)	69.6 (7.17)
Sex: Female, Male (Count of Participants)
Female	1 25%	1 33.3%	3 13.6%	6 27.3%	11 21.6%
Male	3 75%	2 66.7%	19 86.4%	16 72.7%	40 78.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 4.5%	1 2%
Not Hispanic or Latino	4 100%	3 100%	22 100%	21 95.5%	50 98%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 4.5%	1 2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	4 100%	3 100%	22 100%	21 95.5%	50 98%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Mixed Model of Repeated Measures (MMRM) Change From Baseline in Awake Objective Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Day 7	-9.1 (2.7)	-6.6 (2.7)
Day 14	-6.6 (4.5)	-5.8 (4.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.5096
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -10.1 to 5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.8983
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -13.4 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

2. Primary Outcome

Title	Awake Objective Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Baseline	46.2 (43.06)	48.0 (55.17)
Day 7	37.1 (46.52)	41.8 (50.11)
Day 14	39.4 (57.67)	41.9 (44.37)

3. Primary Outcome

Title	Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Day 7	-8.8 (21.81)	-6.6 (13.36)
Day 14	-5.9 (36.76)	-5.7 (19.63)

4. Primary Outcome

Title	Percent Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Day 7	-18.2 (50.06)	-14.1 (31.14)
Day 14	-11.9 (60.00)	6.6 (58.83)

5. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 1)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	19	20
Day 7	-15.6 (4.0)	-11.9 (3.7)
Day 14	-14.9 (6.6)	-13.1 (6.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.5005
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.7
	Confidence Interval	(2-Sided) 95%; -14.6 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.8382
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -19.8 to 16.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 14

6. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 2)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	20	19
Day 7	-2.7 (3.7)	-1.3 (3.8)
Day 14	1.7 (6.2)	1.5 (6.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.8008
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -11.9 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.9805
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -17.6 to 18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 14

7. Secondary Outcome

Title	Responder Analysis of Awake Cough Frequency at Day 7 (Periods 1 & 2 Combined)
Description	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.
Time Frame	Day 7 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	36	37
Day 7: >= 70% reduction	1 25%	1 33.3%
Day 7: >= 50% reduction	8 200%	5 166.7%
Day 7: >= 30% reduction	19 475%	11 366.7%
Day 7: >= 20% reduction	22 550%	13 433.3%

8. Secondary Outcome

Title	Responder Analysis of Awake Cough Frequency at Day 14 (Periods 1 & 2 Combined)
Description	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.
Time Frame	Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	36	38
Day 14: >= 70% reduction	3 75%	1 33.3%
Day 14: >= 50% reduction	11 275%	3 100%
Day 14: >= 30% reduction	18 450%	10 333.3%
Day 14: >= 20% reduction	19 475%	15 500%

9. Secondary Outcome

Title	MMRM Analysis of Change From Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Day 7	-7.1 (1.7)	-4.7 (1.7)
Day 14	-2.5 (3.9)	-4.0 (3.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.3279
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -7.1 to 2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.7772
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -9.2 to 12.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 14

10. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 1)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	19	20
Day 7	-11.8 (2.5)	-8.5 (2.3)
Day 14	-9.1 (5.6)	-10.1 (5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.3493
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -10.1 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.8952
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -14.3 to 16.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 14

11. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 2)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	20	19
Day 7	-2.4 (2.3)	-0.9 (2.4)
Day 14	4.1 (5.3)	2.1 (5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.6597
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -8.1 to 5.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.7880
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -13.1 to 17.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS means difference Day 14

12. Secondary Outcome

Title	24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
Description	24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Baseline	33.6 (33.39)	35.5 (39.99)
Day 7	26.4 (33.46)	30.5 (39.09)
Day 14	30.6 (47.27)	31.2 (34.19)

13. Secondary Outcome

Title	Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Day 7	-6.8 (13.76)	-4.5 (7.78)
Day 14	-2.0 (30.47)	-4.0 (16.79)

14. Secondary Outcome

Title	Percent Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Day 7	-20.4 (49.10)	-14.6 (28.97)
Day 14	-9.4 (59.22)	-9.7 (64.24)

15. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Sleep Cough Frequency (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	38	38
Day 7	-1.8 (1.3)	0.8 (1.3)
Day 14	3.3 (3.4)	0.6 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.1856
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -6.3 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.5658
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; -6.6 to 12.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

16. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Cough Visual Analog Scale (VAS) (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	40
Day 7	-16.3 (3.3)	-8.2 (3.2)
Day 14	-14.3 (4.0)	-8.5 (4.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.0847
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.0
	Confidence Interval	(2-Sided) 95%; -17.2 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.3083
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.8
	Confidence Interval	(2-Sided) 95%; -17.0 to 5.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

17. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Cough Quality of Life Questionnaire (CQLQ) (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Day 7	-2.3 (1.2)	-0.3 (1.2)
Day 14	0.2 (1.2)	0.3 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.2290
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -5.3 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.9794
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -3.5 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

18. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Total Daily Cough Severity Diary (CSD) Score (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Week 1, and Week 2 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Week 1	-1.4 (0.2)	-0.4 (0.2)
Week 2	-1.7 (0.2)	-0.7 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Week 1

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.0050
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.7 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Week 2

19. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Day 7	-3.9 (1.9)	-1.0 (1.9)
Day 14	-2.4 (1.9)	1.6 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.2938
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -8.2 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	MMRM model uses the change from baseline as the dependent variable and includes the period, treatment group (Gefapixant 50 mg, Placebo), visit (Day 7 and Day 14 at each Period), all interactions terms as fixed factors, and baseline as a covariate.
Statistical Test of Hypothesis	p-Value	0.1319
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -9.2 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

20. Secondary Outcome

Title	MMRM Analysis of Change From Baseline in Cough Borg CR10 Scale Score (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Day 7	-0.5 (0.3)	0.1 (0.3)
Day 14	-0.1 (0.4)	0.3 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2175
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.5 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5312
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.4 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS mean difference Day 14

21. Secondary Outcome

Title	Percentage of Participants With Borg CR10 Perception of Breathless Value ≥5 (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who received at least 1 dose of study drug. Two participants that had missing values for Day 14 were excluded.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	48	48
Day 7	41.67 1041.8%	43.75 1458.3%
Day 14	50.00 1250%	43.75 1458.3%

22. Secondary Outcome

Title	Patient's Global Impression of Change (PGIC) Day 7 (Periods 1 & 2 Combined)
Description	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".
Time Frame	Day 7 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Very much improved	3 75%	1 33.3%
Much improved	14 350%	5 166.7%
Minimally improved	12 300%	10 333.3%
No change	7 175%	18 600%
Minimally worse	2 50%	4 133.3%
Much worse	0 0%	1 33.3%
Very much worse	1 25%	1 33.3%

23. Secondary Outcome

Title	Patient's Global Impression of Change (PGIC) Day 15 (Periods 1 & 2 Combined)
Description	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".
Time Frame	Day 15 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	38
Very much improved	5 125%	4 133.3%
Much improved	16 400%	8 266.7%
Minimally improved	8 200%	5 166.7%
No change	5 125%	16 533.3%
Minimally worse	4 100%	3 100%
Much worse	1 25%	2 66.7%
Very much worse	0 0%	0 0%

24. Secondary Outcome

Title	Clinician's Global Impression of Change (CGIC) Day 15 (Periods 1 & 2 Combined)
Description	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".
Time Frame	Day 15 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	38
Very much improved	7 175%	3 100%
Much improved	11 275%	4 133.3%
Minimally improved	13 325%	6 200%
No change	4 100%	18 600%
Minimally worse	2 50%	5 166.7%
Much worse	2 50%	1 33.3%
Very much worse	0 0%	0 0%

25. Secondary Outcome

Title	Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least Six Months
Description	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."
Time Frame	After last treatment, up to Day 15 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	38
Extremely unlikely	2 50%	1 33.3%
Unlikely	4 100%	2 66.7%
Neither	5 125%	4 133.3%
Likely	8 200%	12 400%
Extremely likely	21 525%	19 633.3%

26. Secondary Outcome

Title	Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least One Year
Description	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."
Time Frame	After last treatment, up to Day 15 (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	38
Extremely unlikely	3 75%	1 33.3%
Unlikely	3 75%	2 66.7%
Neither	5 125%	4 133.3%
Likely	11 275%	13 433.3%
Extremely likely	18 450%	18 600%

27. Other Pre-specified Outcome

Title	Pre-dose Baseline of Awake Objective Cough Frequency
Description	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.
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	38
Period 1	50.2 (29.50)	56.1 (71.68)
Period 2	42.5 (53.42)	39.4 (29.19)

28. Other Pre-specified Outcome

Title	Pre-dose Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
Description	24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour cough frequency in Periods 1 and 2 was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	39
Mean (Standard Deviation) [Coughs/hour]	33.6 (33.39)	35.5 (39.99)

29. Other Pre-specified Outcome

Title	Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 1)
Description	24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour cough frequency for Period 1 was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 1)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	19	20
Mean (Standard Deviation) [Coughs/hour]	36.1 (22.18)	42.5 (51.52)

30. Other Pre-specified Outcome

Title	Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 2)
Description	24-hour objective cough frequency = total number of coughs during the monitoring period divided by the total duration for the monitoring period. Baseline 24-hour objective cough frequency for Period 2 was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	20	19
Mean (Standard Deviation) [Coughs/hour]	31.1 (41.84)	28.1 (21.52)

31. Other Pre-specified Outcome

Title	Pre-dose Baseline Sleep Cough Frequency
Description	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. Baseline sleep cough frequency was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	38	38
Mean (Standard Deviation) [Coughs/hour]	8.1 (20.83)	8.5 (21.26)

32. Other Pre-specified Outcome

Title	Pre-dose Baseline Cough VAS (Periods 1 & 2 Combined)
Description	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 was defined as average of screening and baseline cough VAS.
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	39	40
Mean (Standard Deviation) [Score on a scale]	56.0 (24.03)	53.9 (22.80)

33. Other Pre-specified Outcome

Title	Pre-dose Baseline Cough CQLQ (Periods 1 & 2 Combined)
Description	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. Baseline cough CQLQ was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Mean (Standard Deviation) [Score on a scale]	56.5 (13.26)	56.8 (11.25)

34. Other Pre-specified Outcome

Title	Pre-dose Baseline Cough Severity CSD (Periods 1 & 2 Combined)
Description	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.
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	36	32
Mean (Standard Deviation) [Score on a scale]	4.5 (1.75)	4.1 (2.04)

35. Other Pre-specified Outcome

Title	Pre-dose Baseline of UCSD SOBQ (Periods 1 & 2 Combined)
Description	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. Baseline of UCSD SOBQ was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Mean (Standard Deviation) [Score on a scale]	58.0 (26.06)	57.1 (24.63)

36. Other Pre-specified Outcome

Title	Pre-dose Baseline of Cough Borg CR10 Scale Score (Periods 1 & 2 Combined)
Description	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 baseline of cough Borg CR10 was evaluated based on the participant's randomized group (gefapixant or placebo).
Time Frame	Baseline (Day 0) (Period 1 and Period 2)

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized participants who had a baseline and at least 1 post-baseline frequency values, were enrolled into the study under protocol amendment 3, and had otherwise complied with the protocol without any major protocol deviations. Participants enrolled prior to protocol amendment 3 were not included in the efficacy analysis.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description	Gefapixant 50 mg BID for 14 days during 1 of 2 periods	Placebo BID for 14 days during 1 of 2 periods
Measure Participants	40	40
Mean (Standard Deviation) [Score on a scale]	4.4 (3.08)	3.9 (2.56)

Adverse Events

Time Frame	Up to 63 days (9 weeks)
Adverse Event Reporting Description	Analysis population includes all participants who received at least one dose of study drug.
Arm/Group Title	Placebo		Gefapixant 50 mg		Gefapixant 150 mg
Arm/Group Description	Participants received placebo BID for 14 days		Participants received gefapixant 50 mg BID for 10 or 14 days		Participants received gefapixant 150 mg BID for 4 days
All Cause Mortality
	Placebo		Gefapixant 50 mg		Gefapixant 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Gefapixant 50 mg		Gefapixant 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/45 (6.7%)		3/47 (6.4%)		1/4 (25%)
Cardiac disorders
Atrial fibrillations	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
Palpitations	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
General disorders
Chest pain	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
Infections and infestations
Bronchitis	1/45 (2.2%)	1	1/47 (2.1%)	1	1/4 (25%)	1
Pneumonia	2/45 (4.4%)	2	0/47 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dysponea	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
Interstitial Lung Disease	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
Respiratory failure	0/45 (0%)	0	1/47 (2.1%)	1	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Gefapixant 50 mg		Gefapixant 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/45 (26.7%)		39/47 (83%)		3/4 (75%)
Gastrointestinal disorders
Diarrhoea	2/45 (4.4%)	2	3/47 (6.4%)	3	0/4 (0%)	0
Hypoaesthesia oral	0/45 (0%)	0	4/47 (8.5%)	5	0/4 (0%)	0
Paraesthesia oral	0/45 (0%)	0	4/47 (8.5%)	6	0/4 (0%)	0
Nausea	0/45 (0%)	0	5/47 (10.6%)	5	0/4 (0%)	0
Infections and infestations
Respiratory tract infection	0/45 (0%)	0	0/47 (0%)	0	1/4 (25%)	1
Upper respiratory tract infection	0/45 (0%)	0	1/47 (2.1%)	1	1/4 (25%)	1
Urinary tract infection	1/45 (2.2%)	1	3/47 (6.4%)	3	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/45 (0%)	0	0/47 (0%)	0	1/4 (25%)	1
Nervous system disorders
Ageusia	0/45 (0%)	0	11/47 (23.4%)	14	0/4 (0%)	0
Dizziness	0/45 (0%)	0	4/47 (8.5%)	4	0/4 (0%)	0
Dysgeusia	1/45 (2.2%)	1	25/47 (53.2%)	28	0/4 (0%)	0
Hypogeusia	0/45 (0%)	0	5/47 (10.6%)	6	0/4 (0%)	0
Renal and urinary disorders
Pollakiuria	1/45 (2.2%)	1	4/47 (8.5%)	4	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	6/45 (13.3%)	7	6/47 (12.8%)	7	0/4 (0%)	0
Rales	2/45 (4.4%)	2	0/47 (0%)	0	1/4 (25%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No data collected as part of this study will be utilized in any written work, including publications, without the written consent of Sponsor.