Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency

Abstract

Background: Treatment of chronic cough remains a challenge. We hypothesised that inhaled alkaline hypertonic divalent salts (alkaline HDS) might provide relief for refractory chronic cough by laryngeal and tracheal hydration.

Methods: We conducted an exploratory, single-blinded, nasal saline-controlled study in 12 refractory chronic cough patients to examine cough suppression efficacy of an alkaline HDS composition (SC001) at pH 8 or pH 9 administered by nasal inhalation. As control, we used nasal saline with the same hand-held pump spray aerosol device. Each subject was monitored continuously using a digital cough monitor watch for 1 week of baseline, 1 week of control treatment and 1 week of active treatment.

Results: Baseline daily cough rates ranged from 4 to 34 coughs·h^-1 with mean visual analogue score 65±17 pre- and post-baseline testing. Control-adjusted efficacy of cough rate reduction ranged from 15% (p=0.015) (from Day 1) to 23% (p=0.002) (from Day 3). Control-adjusted efficacy was highest with SC001 pH 9 (n=5), ranging from 25% (p=0.03) (from Day 1) to 35% (p=0.02) (from Day 3), and lowest for SC001 pH 8 (n=7), ranging from 9% (p=0.08) (from Day 1) to 16% (p=0.02) (from Day 3). Hourly cough counts and visual analogue score correlated for baseline (r=0.254, p=0.02) and control (r=0.299, p=0.007) monitoring weeks. Treatment improved this correlation (r=0.434, p=0.00006). No adverse events were reported.

Conclusions: Alkaline (pH 9) HDS aerosol is a promising treatment for refractory chronic cough and should be further evaluated.

FIGURE 1

Design of the exploratory clinical study of alkaline hypertonic divalent salt (HDS) aerosol for refractory chronic cough treatment. At each visit (V1, V2, V3 and V4) participants were evaluated with clinical measurements as described in the Methods, but cough counts were recorded throughout the study using the Hyfe cough watch.

FIGURE 2

Box plot showing the hourly cough count distribution and daily-averaged mean and median hourly cough rate during the baseline monitoring period for the day and night hours. Each box plot shows the median, interquartile range (IQR), maximum and minimum values, with each round marker representing the total number of coughs measured for every hour monitored. NS: not significant; *p<0.05; **p<0.01; ***p<0.0001.

FIGURE 3

Scatterplots showing positive correlations between daily visual analogue scale (VAS) measurements and total daily cough count for subjects during the baseline, control and treatment phases. HDS: hypertonic divalent salts.

FIGURE 4

Nasal saline control-adjusted efficacy as a function of assumed day of treatment onset up to Day 4 following first administration after which no significant efficacy change occurs for the entire treatment week. Efficacy of treatment is represented for all subjects (n=12) treated with the alkaline hypertonic divalent salts (HDS) aerosol (SC001) and for those subsets of subjects treated with pH 9 HDS (n=5) or pH 8 HDS (n=7). *: 0.01

FIGURE 5

Per cent reduction in weekly and daily visual analogue score (VAS) post-treatment relative to post-control for the four subjects who received the high alkaline hypertonic divalent salts (HDS) aerosol and successfully administered the aerosol for the entire week of treatment. Per cent VAS reduction for daily VAS is based on the mean VAS of the last 3 days of treatment relative to the VAS of the last day of control testing.