Jayaram L, King P T, Hunt J, Lim M, Park C, Hu E, Dousha L, Ha P, Bartlett J B, Southcott A M, Muruganandan S, Vogrin S, Rees M A, Dean O M, Wong C A
Western Health, Gordon Street, Footscray, VIC, 3011, Australia; University of Melbourne, Parkville, VIC, 3010, Australia.
Monash Medical Centre, Clayton Road, Clayton, VIC, 3068, Australia; Monash University, Wellington Road, Clayton, VIC, 3068, Australia.
Pulm Pharmacol Ther. 2024 Mar;84:102283. doi: 10.1016/j.pupt.2023.102283. Epub 2023 Dec 22.
High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis.
Primary outcome: to assess the efficacy of NAC 2400 mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects.
Participants were randomised to receive 2400 mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed.
The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n = 9) vs placebo (n = 8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV1.56 L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p = 0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups.
High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.
高剂量N-乙酰半胱氨酸(NAC)是一种黏液溶解剂、抗炎和抗氧化剂,在慢性阻塞性肺疾病(COPD)患者的安慰剂对照、双盲随机(RCT)研究以及支气管扩张症的开放随机研究中,已显示出能显著减少病情加重,并改善生活质量。在这项试点、随机、双盲、安慰剂对照研究中,我们希望探究更大规模临床试验的可行性,以及高剂量NAC在支气管扩张症中的抗炎和临床益处。
主要结局:评估6周时每日2400毫克NAC对痰液中性粒细胞弹性蛋白酶(NE)的疗效,NE是病情加重的替代标志物。次要目的包括评估NAC对痰液MUC5B、白细胞介素-8、肺功能、生活质量和不良反应的疗效。
参与者被随机分配接受2400毫克NAC或安慰剂,为期6周。他们接受了3次访视:基线时、第3周和第6周,在此期间评估临床和痰液指标。
由于新冠疫情,该研究提前终止。总共招募了30名患者中的24名,其中17名完成了研究的所有方面。鉴于此,进行了符合方案分析:NAC组(n = 9)与安慰剂组(n = 8):平均年龄分别为72岁和62岁;男性比例分别为44%和50%;基线时FEV1中位数分别为56升(平均预测值的71.5%)和2.29升(平均预测值的82.2%)。在第6周时,NAC组痰液NE相对于安慰剂组下降了47%(平均倍数差异(95%CI):0.53(0.12,2.42));与安慰剂相比,NAC使MUC5B增加了48%。与安慰剂相比,NAC在第6周时使肺功能FVC显著改善(平均倍数差异(95%CI):1.10(1.00,1.20),p = 0.045)。呼吸和社会功能领域的支气管扩张症生活质量指标显示出具有临床意义的改善,其中社会功能达到统计学显著性。两组的不良反应相似。
高剂量NAC具有抗炎益处,并能改善生活质量和肺功能指标方面的情况。它安全且耐受性良好。现在有必要进行进一步更大规模的安慰剂对照RCT研究,以检验其在减少病情加重方面的作用。