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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.

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