Treatment of Persistent Cough in Subjects with Idiopathic Pulmonary Fibrosis (IPF) with Gefapixant, a P2X3 Antagonist, in a Randomized, Placebo-Controlled Clinical Trial

Fernando J Martinez; Amna Sadaf Afzal; Jaclyn A Smith; Anthony P Ford; Jerry Jing Li; Yuping Li; Michael M Kitt; Chronic Cough in IPF Study Group

doi:10.1007/s41030-021-00162-9

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.

Authors

Fernando J Martinez¹, Amna Sadaf Afzal², Jaclyn A Smith³, Anthony P Ford², Jerry Jing Li², Yuping Li⁴, Michael M Kitt²; Chronic Cough in IPF Study Group

Collaborators

Chronic Cough in IPF Study Group:
Iftikhar Hussain, Mandel Sher, Selwyn Spangenthal, Faisal Fakih, Mark Gotfried, Kevin Flaherty, Lisa Lancaster, Maureen Horton, Robert Kaner, Kapil Patel, Mary Beth Scholand, Robert Sussman, Ganesh Raghu, Imre Noth, Michael Denenberg, Shahzad Ahmad, Neil Ettinger, Vivek Iyer, Murali Ramaswamy

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York City, NY, USA. fjm2003@med.cornell.edu.
² Merck & Co., Inc., Kenilworth, NJ, USA.
³ Division of Infection, Immunity and Respiratory Medicine, University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK.
⁴ GetStat Solutions, LLC, Palo Alto, CA, USA.

Abstract

Introduction: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF.

Methods: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study.

Results: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia).

Conclusions: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study.

Trial registration: NCT02502097.

Keywords: AF-219; Chronic cough; Gefapixant; Idiopathic pulmonary fibrosis; MK-7264; P2X3 receptor antagonist; Treatment-refractory chronic cough.

Associated data

ClinicalTrials.gov/NCT02502097

Grants and funding

WT_/Wellcome Trust/United Kingdom