Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial

Abstract

Evidence for the treatment of patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) is limited. The efficacy of N-acetylcysteine (an antioxidant and mucolytic agent) for patients with mild-to-moderate COPD is uncertain. In this multicentre, randomised, double-blind, placebo-controlled trial, we randomly assigned 968 patients with mild-to-moderate COPD to treatment with N-acetylcysteine (600 mg, twice daily) or matched placebo for two years. Eligible participants were 40-80 years of age and had mild-to-moderate COPD (forced expiratory volume in 1 second [FEV₁] to forced vital capacity ratio <0.70 and an FEV₁ ≥ 50% predicted value after bronchodilator use). The coprimary outcomes were the annual rate of total exacerbations and the between-group difference in the change from baseline to 24 months in FEV₁ before bronchodilator use. COPD exacerbation was defined as the appearance or worsening of at least two major symptoms (cough, expectoration, purulent sputum, wheezing, or dyspnoea) persisting for at least 48 hours. Assessment of exacerbations was conducted every three months, and lung function was performed annually after enrolment. The difference between the N-acetylcysteine group and the placebo group in the annual rate of total exacerbation were not significant (0.65 vs. 0.72 per patient-year; relative risk [RR], 0.90; 95% confidence interval [CI], 0.80-1.02; P = 0.10). There was no significant difference in FEV₁ before bronchodilator use at 24 months. Long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improved lung function in patients with mild-to-moderate COPD. Chinese Clinical Trial Registration: ChiCTR-IIR-17012604.

Fig. 1. Study flow diagram.

Patients who underwent randomization, were treated with at least one dose of N-acetylcysteine or placebo, and had available exacerbation assessment data at any planned follow-up visit were included in the full analysis set for exacerbation.

Fig. 2. Acute exacerbation of COPD during the study (full analysis set for exacerbation).

Data are mean ± standard error. COPD=chronic obstructive pulmonary disease. The relative risk was calculated using Poisson regression, with correction for exposure to the trial regimen, overdispersion, age, sex, body mass index, smoking status, COPD exacerbations in the previous year, COPD treatment at baseline and center. The error bars indicate 95% confidence intervals.

Fig. 3. Mean forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) before and after bronchodilator use over time (full analysis set for lung function).

Mixed-effects model for repeated measures was used to compare the differences in lung function before and after bronchodilator use at each visit between the two groups. The error bars indicate ± standard error. N-acetylcysteine did not significantly improve FEV₁ before bronchodilator use when compared with placebo at 24 months (mean difference: 16 ml, 95% confidence interval, −69 to 100 ml; P = 0.72) and at each visit (P > 0.05 for all comparisons) (A). N-acetylcysteine did not significantly improve FVC when compared with placebo at 12 or 24 months (P > 0.05 for all comparisons) (B).

Fig. 4. Forest plot of acute exacerbation of COPD according to subgroups (full analysis set for exacerbation).

COPD=chronic obstructive pulmonary disease. GOLD=Global Initiative for Chronic Obstructive Lung Disease. CI=confidence interval. mMRC=modified Medical Research Council. CAT=chronic obstructive pulmonary disease assessment test. Relative risk and 95% confidence intervals are shown and the error bars indicate 95% confidence intervals. The relative risk was calculated using Poisson regression, with correction for exposure to the trial regimen, overdispersion, age, sex, body mass index, smoking status, COPD exacerbations in the previous year, COPD treatment at baseline and center.