Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, Norfolk, United Kingdom.
Department of Respiratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk, United Kingdom.
JAMA. 2020 Dec 8;324(22):2282-2291. doi: 10.1001/jama.2020.22960.
Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole).
To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF.
DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up).
Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily.
The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King's Brief Interstitial Lung Disease questionnaire scores).
Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]).
Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo.
ISRCTN Identifier: ISRCTN17464641.
特发性肺纤维化 (IPF) 预后较差，治疗选择有限。IPF 患者的肺部微生物群发生改变，肺部细菌负担与死亡率相关；先前的研究表明复方新诺明（甲氧苄啶-磺胺甲噁唑）有益。
确定复方新诺明在中重度 IPF 患者中的疗效。
设计、地点和参与者：这是一项在英国 39 个特发性间质性肺病中心进行的、342 名 IPF 患者（呼吸困难（改良英国医学研究理事会呼吸困难量表评分>1）和肺功能受损（用力肺活量≤75%预计值））参与的、双盲、安慰剂对照、平行随机试验。试验于 2015 年 4 月（首次就诊）至 2019 年 4 月（最后一次随访）进行。
研究参与者被随机分为每日两次口服 960mg 复方新诺明（n=170）或匹配的安慰剂（n=172），持续 12 至 42 个月。所有患者均每日口服 5mg 叶酸。
主要结局是死亡（所有原因）、肺移植或首次非选择性住院的时间。有 15 个次要结局，包括主要终点呼吸相关事件、肺功能（用力肺活量和气体转移）和患者报告的结局（改良英国医学研究理事会呼吸困难量表、5 级欧洲五维健康量表问卷、咳嗽严重程度、莱斯特咳嗽问卷和金氏间质性肺病问卷评分）的各个组成部分。
在 342 名随机分组的个体中（平均年龄 71.3 岁；46[13%]名女性），283 名（83%）完成了试验。中位（四分位距）随访时间为 1.02（0.35-1.73）年。随机分配至复方新诺明组和安慰剂组的参与者中，每人每年的事件发生率分别为 0.45（84/186）和 0.38（80/209），风险比为 1.2（[95%CI，0.9-1.6]；P=0.32）。其他事件结局、肺功能或患者报告的结局均无统计学差异。复方新诺明组有 696 例不良事件（恶心[n=89]、腹泻[n=52]、呕吐[n=28]和皮疹[n=31]），安慰剂组有 640 例不良事件（恶心[n=67]、腹泻[n=84]、呕吐[n=20]和皮疹[n=20]）。
在中重度 IPF 患者中，与安慰剂相比，口服复方新诺明治疗并未降低死亡、移植或非选择性住院的复合结局。
ISRCTN 标识符：ISRCTN85322153.
