The Efficacy of Bradanicline in Refractory Chronic Cough

Abstract

Background: Several clinical studies have implicated nicotine in reducing cough reflex sensitivity in both healthy smoking and non-smoking subjects. Bradanicline, a highly selective α7 nicotinic acetylcholine receptor (nAChR) agonist, may therefore be effective for refractory chronic cough (RCC), possibly through sensory gating in the central nervous systems.

Rationale: To evaluate the efficacy of bradanicline in RCC patients.

Methods: This randomized, double-blinded, placebo-controlled, crossover study recruited 46 RCC patients (39 females, mean age 63 years, median cough duration 18 years) from November 2018 to February 2019. Patients were allocated to bradanicline-placebo or placebo-bradanicline, 1:1 ratio, after screening for a minimum ≥10 coughs/hr. Following an initial loading dose (50mg bradanicline or matched placebo), study treatment was escalated weekly from 25mg to 75mg, and then 150mg or a matched placebo regimen for a total of 3 weeks of treatment. After a 14-day washout, patients were crossed over. Cough frequency was monitored for 24 hours (VitaloJAK). The primary endpoint was the relationship between bradanicline dose and awake cough frequency (ACF).

Results: All but one patient completed the study and 409/414 cough recordings were available for analysis. Mean ACF at baseline was 36.4 (SD 29.3) coughs/hour. Neither bradanicline nor placebo reduced ACF, with no meaningful difference between the two treatments. Patient reported outcomes also showed no treatment effects. The frequency of adverse effects was similar for bradanicline (n = 16) and placebo (n = 17).

Conclusions: Despite good tolerability, escalating doses of bradanicline did not reduce awake cough frequency in RCC patients compared with placebo.