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. 2021 Aug 2;7(3):00269-2021.
doi: 10.1183/23120541.00269-2021. eCollection 2021 Jul.

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

Valerie J Ludbrook  1 , Kate E Hanrott  1 , James L Kreindler  2 , Joanna E Marks-Konczalik  1 , Nick P Bird  1 , Debbie A Hewens  1 , Misba Beerahee  1 , David J Behm  2 , Alyn Morice  3 , Lorcan McGarvey  4 , Sean M Parker  5 , Surinder S Birring  6 , Jaclyn Smith  7
Affiliations

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

Valerie J Ludbrook et al. ERJ Open Res. .

Abstract

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 washout between treatments. Pharmacokinetic samples were collected for analysis of GSK2798745 at end of study. The primary end-point 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 61 years; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% credible interval: -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.

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Conflict of interest statement

Conflict of interest: V.J. Ludbrook reports salary from and shares in GlaxoSmithKline, and part-funding of the present study 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). Conflict of interest: K.E. Hanrott is an employee of and shareholder in GlaxoSmithKline. Conflict of interest: J.L. 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: N.P. Bird has nothing to disclose. Conflict of interest: D.A. Hewens is an employee of and shareholder in GlaxoSmithKline. Conflict of interest: M. Beerahee has nothing to disclose. Conflict of interest: D.J. Behm reports this project has been funded in part with Federal funds from the Department of Health and Human Services (Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority) under contract number HHSO100201700009C; and salary and bonuses from, and stock in GlaxoSmithKline. Conflict of interest: A. Morice reports grants from GSK during the conduct of the study; and grants and personal fees from Merck, Shionogi, Bayer, Bellus and NeRRi outside the submitted work. Conflict of interest: L. McGarvey reports personal fees from GSK, grants and personal fees from MERCK, personal fees from Shionogi, Bayer, Bellus Health and Nocion, grants and personal fees from Chiesi, and personal fees from Applied Clinical Intelligence, outside the submitted work. Conflict of interest: S.M. Parker has nothing to disclose. Conflict of interest: S.S. Birring reports personal fees from GSK, Merck, Bellus, Bayer, Shionogi, Nerre, Nocion and Boehringer Ingelheim, and grants from Merck, outside the submitted work. Conflict of interest: J. Smith reports grants from GlaxoSmithKline during the conduct of the study; grants and personal fees from NeRRe Pharmaceuticals, Menlo and Bayer, personal fees from Boehringer Ingleheim, nonfinancial support from Vitalograph, personal fees from Cheisi and Bellus, grants and personal fees from Axalbion, personal fees from AstraZeneca, grants and personal fees from Merck, and personal fees from Algernon and Nocion, outside the submitted work. In addition, J. Smith has a patent (A method for generating output data) licensed.

Figures

FIGURE 1
FIGURE 1
Study design. Participants were randomised to receive either 4.8 mg GSK2798745 on Day 1, followed by 2.4 mg once daily for 6 days, or matching placebo once daily for 7 days in the first treatment period, followed by the alternative regimen in the second treatment period.
FIGURE 2
FIGURE 2
Consolidated Standards of Reporting Trials participant disposition.
FIGURE 3
FIGURE 3
Individual change from baseline cough counts over day-time and 24-h time periods. Individual patient data are plotted on each line.
FIGURE 4
FIGURE 4
Patient reported outcome measure results for Severity of Cough visual analogue scale (VAS), Urge to Cough VAS and Leicester Cough Questionnaire (LCQ), presented as mean±95% CI.
See this image and copyright information in PMC

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