TY - JOUR
T1 - Aprepitant for Cough in Lung Cancer A Randomized Placebo-controlled Trial and Mechanistic Insights
AU - Smith, Jaclyn A
AU - Harle, Amélie
AU - Dockry, Rachel
AU - Holt, Kimberley
AU - Russell, Philip
AU - Molassiotis, Alex
AU - Yorke, Janelle
AU - Robinson, Ryan
AU - Birrell, Mark A.
AU - Belvisi, Maria G.
AU - Blackhall, Fiona
N1 - Funding Information:
Supported by National Institute of Health Research (NIHR) through a Doctoral Research Fellowship awarded to A.H. (DRF-2010-03-55) and by donations from the North West Lung Charity and an unrestricted grant from Nerre Pharmaceuticals. The study also received support from the NIHR Manchester Clinical Research Facility (Wythenshawe and Christie sites). R.R. is supported by Biotechnology and Biological Sciences Research Council Studentship. J.A.S. and M.G.B. are supported by a Wellcome Investigator Award (207504/B/17/Z). J.A.S., J.Y., and F.B. are also funded by the Manchester Biomedical Research Centre, and J.A.S. is an NIHR Senior Investigator.
Publisher Copyright:
Copyright © 2021 by the American Thoracic Society
PY - 2021/3/15
Y1 - 2021/3/15
N2 - Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough. Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue. Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism. Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (67.7); 60% were female and 80% had non–small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8–37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7–44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1–86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P–induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145). Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.
AB - Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough. Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue. Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism. Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (67.7); 60% were female and 80% had non–small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8–37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7–44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1–86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P–induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145). Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.
KW - Cough monitoring
KW - Neurokinin 1
KW - Substance P
U2 - 10.1164/rccm.202006-2359OC
DO - 10.1164/rccm.202006-2359OC
M3 - Article
C2 - 32966755
SN - 1073-449X
VL - 203
SP - 737
EP - 745
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 6
ER -