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

NCT02349425 | Completed Phase 2 Results FDA Drug

• 4 other identifiers: 7264-010AF219-010MK-7264-0102015-000474-35
• Study Type: interventional
• Target: 59
• Locations: 0 countries
• Sites: N/A

Brief Summary

A randomized, double-blind, placebo-controlled, crossover, dose escalation study to assess the efficacy and tolerability of gefapixant (AF-219; MK-7264) in participants with refractory chronic cough.

Conditions

Refractory Chronic Cough

Outcome Measures

Primary Outcomes (6)

• Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1

  Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

• Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2

  Awake Objective Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

• Percent Change From Baseline in Awake Cough Frequency for Cohort 1

  Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

• Percent Change From Baseline in Awake Cough Frequency for Cohort 2

  Awake Objective Cough Frequency (per hour) is the total number of cough events during the monitoring period (in general, 24-hr interval) the participant is awake divided by the total duration (in hours) for the monitoring period the participant is awake. 24-hour sound recordings were collected using a digital recording device. Percent Change in Awake Cough Frequency is the change from baseline in awake cough frequency x 100, divided by baseline awake cough frequency. A negative result indicates a decrease in cough frequency, while a positive result indicates an increase in cough frequency.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

• Responder Analysis of Awake Cough Frequency for Cohort 1

  Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

• Responder Analysis of Awake Cough Frequency for Cohort 2

  Participants were classified as responders based on the magnitude of the percent change from baseline in Awake Objective cough frequency: 1. ≥70% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤-70.0%; 0 Otherwise; 2. ≥50% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -50.0%; 0 Otherwise; 3. ≥30% Reduction=1 if Percent Change from Baseline in cough frequency at the end of the dosing interval ≤ -30.0%; 0 Otherwise. These responder definitions were not mutually exclusive. A participant who achieved a 1 for ≥70% Reduction for a particular period and dosing interval, were by definition, classified as ≥50% Reduction and ≥ 30% Reduction.

  Period 1 (while awake): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Secondary Outcomes (11)

• Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1

  Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses

• Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2

  Period 1 (while awake): baseline (Day 0) and 0-8 hours after Day 4, 8, 12 & 16 doses; Period 2 (while awake): baseline (Day 22) and 0-8 hours after Day 26, 30, 34 and 38 doses

• Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1

  Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses

• Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2

  Period 1: baseline (Day 0) and 0-24 hours after Day 4, 8, 12 & 16 doses; Period 2: baseline (Day 22) and 0-24 hours after Day 26, 30, 34 and 38 doses

• Change From Baseline in Sleep Cough Frequency - Cohort 1

  Period 1 (while asleep): baseline (Day 0) and 24 hours after Day 4, 8, 12 & 16 doses; Period 2 (while asleep): baseline (Day 22) and 24 hours after Day 26, 30, 34 and 38 doses

Other Outcomes (7)

• Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2

  24 hours (while awake) on Days 0 and 22 (Baseline)

• Baseline (Predose) Awake (0 - 8 Hours) Cough Frequency for Cohort 1 and Cohort 2

  First 8 hours (while awake) on Days 0 and 22 (Baseline)

• Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2

  24 hours (while awake) on Days 0 and 22 (Baseline)

Study Arms (4)

Cohort 1: Gefapixant>Placebo

EXPERIMENTAL

50, 100, 150, and 200 mg gefapixant twice daily (BID) for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

Drug: Gefapixant; Drug: Placebo (for gefapixant)

Cohort 1: Placebo>Gefapixant

EXPERIMENTAL

Placebo BID for 16 days in Period 1 and gefapixant 50, 100, 150, and 200 mg BID for 4 days each in Period 2. For Cohort 1, there was a 3 to 7 day washout period between treatment periods.

Drug: Gefapixant; Drug: Placebo (for gefapixant)

Cohort 2: Gefapixant>Placebo

EXPERIMENTAL

Gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 1 and placebo BID for 16 days in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.

Drug: Gefapixant; Drug: Placebo (for gefapixant)

Cohort 2: Placebo>Gefapixant

EXPERIMENTAL

Placebo BID for 16 days in Period 1 and gefapixant 7.5, 15, 30, and 50 mg BID for 4 days each in Period 2. For Cohort 2, there was a 14 to 21 day washout period between treatment periods.

Drug: Gefapixant; Drug: Placebo (for gefapixant)

Interventions

Gefapixant DRUG

Gefapixant 7.5 and 50mg tablets administered orally

Also known as: AF-219, MK-7264

Cohort 1: Gefapixant>Placebo; Cohort 1: Placebo>Gefapixant; Cohort 2: Gefapixant>Placebo; Cohort 2: Placebo>Gefapixant

Placebo (for gefapixant) DRUG

Placebo to gefapixant 7.5 and 50mg tablets administered orally

Cohort 1: Gefapixant>Placebo; Cohort 1: Placebo>Gefapixant; Cohort 2: Gefapixant>Placebo; Cohort 2: Placebo>Gefapixant

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chest radiograph or computed tomography (CT) thorax within the last 12 months not demonstrating any abnormality considered to be significantly contributing to the chronic cough
• Refractory chronic cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip or unexplained cough: a cough for which no objective evidence of an underlying trigger can be determined after investigation
• Score of ≥ 40 mm on the Cough Severity Visual Analog Scale (VAS) at Screening
• Women of child-bearing potential must use 2 forms of acceptable birth control method from Screening through the Follow-Up Visit.
• Male participants and their partners of child-bearing potential must use 2 methods of acceptable birth control from Screening until 3 months after the last dose of study drug.
• Written informed consent.
• Willing and able to comply with all aspects of the protocol.

You may not qualify if:

• Current smoker
• Individuals who have given up smoking within the past 6 months, or those with \>20 pack-year smoking history
• Treatment with an angiotensin converting enzyme (ACE)-inhibitor as the potential cause of a participant's cough, or requiring treatment with an ACE-inhibitor during the study or within 4 weeks prior to the Baseline Visit (Day 0)
• Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) \< 60%
• History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0)
• History of opioid use within 1 week of the Baseline Visit (Day 0)
• Requiring concomitant therapy with prohibited medications
• Body mass index (BMI) \<18 kg/m\^2 or ≥ 37 kg/m\^2
• History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including participants with \<3 excised basal cell carcinomas)
• History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years
• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection)
• Screening systolic blood pressure (SBP) \>160 mmHg or a diastolic blood pressure (DBP) \>90 mmHg
• Clinically significant abnormal electrocardiogram (ECG) at Screening
• Personal or family history of congenital long QT syndrome or family history of sudden death
• Cardiac pacemaker

Sponsors & Collaborators

• Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead

Related Publications (1)

• Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, Holt K, Sen S, Sher MR, Ford AP. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020 Mar 20;55(3):1901615. doi: 10.1183/13993003.01615-2019. Print 2020 Mar.

  PMID: 31949115 RESULT

Related Links

• P2X3 Receptor Antagonist (AF-219) in Refractory Chronic Cough: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Study

MeSH Terms

Conditions

Chronic Cough

Interventions

Gefapixant

Condition Hierarchy (Ancestors)

Cough; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2015
• First Posted: January 28, 2015
• Study Start: March 9, 2015
• Primary Completion: February 1, 2016
• Study Completion: February 9, 2016
• Last Updated: October 22, 2020
• Results First Posted: October 22, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share