Clinical trial NCT02502097: A Study of Gefapixant (AF-219/MK-7264) in Participants With Idiopathic Pulmonary Fibrosis (IPF) With Persistent Cough (MK-7264-016)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Cough
Lead sponsor: Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2015-07-20
Enrollment: 51
Sex: ALL
Minimum age (years): 40
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 of gefapixant (AF-219) in participants with Idiopathic Pulmonary Fibrosis (IPF) with persistent cough.

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.

Eligibility criteria: 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 0)
* 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

Primary outcomes:
measure: Mixed Model of Repeated Measures (MMRM) Change From Baseline in Awake Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Awake Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Percent Change From Baseline of Awake Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
Secondary outcomes:
measure: MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 1)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1)
measure: MMRM Analysis of Change From Baseline in Awake Objective Cough Frequency (Period 2)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 2)
measure: Responder Analysis of Awake Cough Frequency at Day 7 (Periods 1 & 2 Combined)
timeFrame: Day 7 (Period 1 and Period 2)
measure: Responder Analysis of Awake Cough Frequency at Day 14 (Periods 1 & 2 Combined)
timeFrame: Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 1)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1)
measure: MMRM Analysis of Change From Baseline in 24-hour Objective Cough Frequency (Period 2)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 2)
measure: 24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Percent Change From Baseline of 24-hour Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in Sleep Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in Cough Visual Analog Scale (VAS) (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in Cough Quality of Life Questionnaire (CQLQ) (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in Total Daily Cough Severity Diary (CSD) Score (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Week 1, and Week 2 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: MMRM Analysis of Change From Baseline in Cough Borg CR10 Scale Score (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Percentage of Participants With Borg CR10 Perception of Breathless Value ≥5 (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0), Day 7, and Day 14 (Period 1 and Period 2)
measure: Patient's Global Impression of Change (PGIC) Day 7 (Periods 1 & 2 Combined)
timeFrame: Day 7 (Period 1 and Period 2)
measure: Patient's Global Impression of Change (PGIC) Day 15 (Periods 1 & 2 Combined)
timeFrame: Day 15 (Period 1 and Period 2)
measure: Clinician's Global Impression of Change (CGIC) Day 15 (Periods 1 & 2 Combined)
timeFrame: Day 15 (Period 1 and Period 2)
measure: Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least Six Months
timeFrame: After last treatment, up to Day 15 (Period 1 and Period 2)
measure: Taste Acceptability Questionnaire: Number of Participants That Were Likely to Take Study Medication For At Least One Year
timeFrame: After last treatment, up to Day 15 (Period 1 and Period 2)
Other outcomes:
measure: Pre-dose Baseline of Awake Objective Cough Frequency
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline 24-hour Objective Cough Frequency (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 1)
timeFrame: Baseline (Day 0) (Period 1)
measure: Pre-dose Baseline of 24-hour Objective Cough Frequency (Period 2)
timeFrame: Baseline (Day 0) (Period 2)
measure: Pre-dose Baseline Sleep Cough Frequency
timeFrame: Baseline (Day 0)
measure: Pre-dose Baseline Cough VAS (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline Cough CQLQ (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline Cough Severity CSD (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline of UCSD SOBQ (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
measure: Pre-dose Baseline of Cough Borg CR10 Scale Score (Periods 1 & 2 Combined)
timeFrame: Baseline (Day 0) (Period 1 and Period 2)
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Martinez FJ, Afzal AS, Smith JA, Ford AP, Li JJ, Li Y, Kitt MM; Chronic Cough in IPF Study Group. Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial. Pulm Ther. 2021 Dec;7(2):471-486. doi: 10.1007/s41030-021-00162-9. Epub 2021 Jun 21.