Clinical trial NCT02349425: A Dose Escalation Study of Gefapixant (AF-219/MK-7264) in Refractory Chronic Cough (MK-7264-010)
Official title: A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects With Refractory Chronic Cough
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Refractory Chronic Cough
Lead sponsor: Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2015-01-28
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* Significantly abnormal laboratory tests at Screening
* Breastfeeding
* Treatment with an investigational drug (except gefapixant) or biologic within 60 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

Primary outcomes:
measure: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
timeFrame: 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
measure: Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
timeFrame: 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
measure: Percent Change From Baseline in Awake Cough Frequency for Cohort 1
timeFrame: 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
measure: Percent Change From Baseline in Awake Cough Frequency for Cohort 2
timeFrame: 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
measure: Responder Analysis of Awake Cough Frequency for Cohort 1
timeFrame: 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
measure: Responder Analysis of Awake Cough Frequency for Cohort 2
timeFrame: 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:
measure: Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 1
timeFrame: 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
measure: Change From Baseline in Awake (0-8 Hours) Objective Cough Frequency for Cohort 2
timeFrame: 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
measure: Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 1
timeFrame: 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
measure: Change From Baseline in Total (24 Hours) Cough Frequency - Cohort 2
timeFrame: 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
measure: Change From Baseline in Sleep Cough Frequency - Cohort 1
timeFrame: 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
measure: Change From Baseline in Sleep Cough Frequency - Cohort 2
timeFrame: 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
measure: Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1
timeFrame: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
measure: Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2
timeFrame: Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39
measure: Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2
timeFrame: Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39
measure: Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1
timeFrame: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
measure: Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2
timeFrame: Screening; Period 1: baseline (Day 0) and Day 4, 8, 12 & 16; Period 2: baseline (Day 22) and Day 26, 30, 34, 38 and 39
Other outcomes:
measure: Baseline (Predose) Awake Objective Cough Frequency for Cohort 1 and Cohort 2
timeFrame: 24 hours (while awake) on Days 0 and 22 (Baseline)
measure: Baseline (Predose) Awake (0 - 8 Hours) Cough Frequency for Cohort 1 and Cohort 2
timeFrame: First 8 hours (while awake) on Days 0 and 22 (Baseline)
measure: Baseline (Predose) Total (24-hour) Cough Frequency for Cohort 1 and Cohort 2
timeFrame: 24 hours (while awake) on Days 0 and 22 (Baseline)
measure: Baseline (Predose) for Sleep Cough Frequency for Cohort 1 and Cohort 2
timeFrame: First 8 hours (while asleep) on Days 0 and 22 (Baseline)
measure: Baseline (Predose) for the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1 and Cohort 2
timeFrame: Baseline (Days 0 and 22)
measure: Baseline (Predose) for the Acute Leicester Cough Questionnaire (LCQ) Instrument for Cohort 1 and Cohort 2
timeFrame: Days 0 and 22 (Baseline)
measure: Baseline (Predose) for Cough Visual Analogue Scale (VAS) for Cohort 1 and Cohort 2
timeFrame: Screening, Days 0 and 22 (Baseline)
Locations:
Study officials:
affiliation: Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.