PT  - JOURNAL ARTICLE
AU  - Valerie J. Ludbrook
AU  - Kate E. Hanrott
AU  - James L. Kreindler
AU  - Joanna E. Marks-Konczalik
AU  - Nick P. Bird
AU  - Debbie A. Hewens
AU  - Misba Beerahee
AU  - David J. Behm
AU  - Alyn Morice
AU  - Lorcan McGarvey
AU  - Sean M Parker
AU  - Surinder S Birring
AU  - Jaclyn Smith
TI  - Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough
AID  - 10.1183/23120541.00269-2021
DP  - 2021 Jan 01
TA  - ERJ Open Research
PG  - 00269-2021
4099  - http://openres.ersjournals.com/content/early/2021/06/11/23120541.00269-2021.short
4100  - http://openres.ersjournals.com/content/early/2021/06/11/23120541.00269-2021.full
AB  - Objective Airway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough.Methods A two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a wash-out between treatments. PK samples were collected for analysis of GSK2798745 at end of study. The primary endpoint was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing.Results Interim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (Mean 61yrs; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% CrI: −3%, +85%) numerical increase for GSK2798745 compared to placebo.Conclusion There was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: Dr. Ludbrook reports other from GlaxoSmithKline, other from US Federal Government funds from the Department of Health and Human Services (Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority) , during the conduct of the study; .Conflict of interest: Dr. Hanrott reports personal fees from GlaxoSmithKline, during the conduct of the study; .Conflict of interest: Dr. Kreindler is a full-time employee of and stockholder in AstraZeneca, and was a full-time employee of GlaxoSmithKline during the conduct of the study.Conflict of interest: Dr. Joanna E. Marks-Konczalik.Conflict of interest: Mr. Bird has nothing to disclose.Conflict of interest: D. Hewens reports personal fees from GlaxoSmithKline, during the conduct of the study; .Conflict of interest: Dr. Beerahee has nothing to disclose.Conflict of interest: Mr. Behm reports other from Biomedical Advanced Research and Development Authority (BARDA), during the conduct of the study; personal fees from GlaxoSmithKline (GSK), outside the submitted work; .Conflict of interest: Dr. Morice reports grants from GSK, during the conduct of the study; grants and personal fees from Merck, grants and personal fees from Shionogi, grants and personal fees from Bayer, grants and personal fees from Bellus, grants and personal fees from NeRRi, outside the submitted work; .Conflict of interest: Dr. McGarvey reports personal fees from GSK, grants and personal fees from MERCK, personal fees from Shionogi, personal fees from Bayer, personal fees from Bellus Health, personal fees from Nocion, grants and personal fees from Chiesi , personal fees from Applied Clinical Intelligence, outside the submitted work; .Conflict of interest: Dr. Parker has nothing to disclose.Conflict of interest: Dr. Birring reports personal fees from GSK, personal fees from Merck, personal fees from Bellus, personal fees from Bayer, personal fees from Shionogi, personal fees from Nerre, personal fees from Nocion, personal fees from Boehringer Ingelheim, grants from Merck, outside the submitted work; .Conflict of interest: Dr. Smith reports grants from GlaxoSmithKline, during the conduct of the study; grants and personal fees from NeRRe Pharmaceuticals, grants and personal fees from Menlo, grants and personal fees from Bayer, personal fees from Boehringer Ingleheim, non-financial support from Vitalograph, personal fees from Cheisi, personal fees from Bellus, grants and personal fees from Axalbion, personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Algernon, personal fees from Nocion, outside the submitted work; In addition, Dr. Smith has a patent A method for generating output data licensed.Dr. Smith reports grants from GlaxoSmithKline, during the conduct of the study; grants and personal fees from NeRRe Pharmaceuticals, grants and personal fees from Menlo, grants and personal fees from Bayer, personal fees from Boehringer Ingleheim, non-financial support from Vitalograph, personal fees from Bellus, grants and personal fees from Axalbion, personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Algernon, personal fees from Nocion, personal fees from Attenua, personal fees from Shionogi, outside the submitted work; In addition, Dr. Smith has a patent A method for generating output data licensed.