A Dose Escalation Study to Assess the Efficacy and Tolerance of AF-219 in Subjects With Refractory Chronic Cough
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 59
- 主要终点
- Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Cohort 1: Gefapixant>Placebo
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.
干预措施: Gefapixant (Drug)
Cohort 1: Gefapixant>Placebo
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.
干预措施: Placebo (for gefapixant) (Drug)
Cohort 1: Placebo>Gefapixant
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.
干预措施: Gefapixant (Drug)
Cohort 1: Placebo>Gefapixant
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.
干预措施: Placebo (for gefapixant) (Drug)
Cohort 2: Gefapixant>Placebo
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.
干预措施: Gefapixant (Drug)
Cohort 2: Gefapixant>Placebo
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.
干预措施: Placebo (for gefapixant) (Drug)
Cohort 2: Placebo>Gefapixant
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.
干预措施: Gefapixant (Drug)
Cohort 2: Placebo>Gefapixant
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.
干预措施: Placebo (for gefapixant) (Drug)
结局指标
主要结局
Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 1
时间窗: 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
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.
Change in Awake Objective Cough Frequency on Log-transformed Scale - Cohort 2
时间窗: 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
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.
Percent Change From Baseline in Awake Cough Frequency for Cohort 1
时间窗: 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
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.
Percent Change From Baseline in Awake Cough Frequency for Cohort 2
时间窗: 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
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.
Responder Analysis of Awake Cough Frequency for Cohort 1
时间窗: 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
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.
Responder Analysis of Awake Cough Frequency for Cohort 2
时间窗: 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
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.
次要结局
- 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)
- Change From Baseline in Sleep Cough Frequency - Cohort 2(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)
- Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 1(Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39)
- Change From Baseline of the Mean Total Daily Cough Severity Diary (CSD) Score for Cohort 2(Screening; Period 1: baseline (Day 0) and Days 1-17; Period 2: baseline (Day 22) and Days 23-39)
- Change From Baseline at End of Treatment Period Leicester Cough Questionnaire (LCQ): Individual Domain and Total Scores for Cohort 1 and 2(Period 1: Day 0 (baseline) and Day 17; Period 2: Day 22 (baseline) and Day 39)
- Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 1(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)
- Change From Baseline of Cough Visual Analogue Scale (VAS) Score for Cohort 2(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)