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

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.

• Authors: Valerie J Ludbrook, Kate E Hanrott, James L Kreindler, Joanna E Marks-Konczalik, Nick P Bird, Debbie A Hewens, Misba Beerahee, David J Behm, Alyn Morice, Lorcan McGarvey, Sean M Parker, Surinder S Birring, Jaclyn Smith
• Journal: ERJ open research (ERJ Open Res) Vol. 7 Issue 3 (Jul 2021) ISSN: 2312-0541 [Print] England
• PMID: 34350286 (Publication Type: Journal Article)
• Copyright: Copyright ©The authors 2021.