一项妥布霉素吸入溶液治疗支气管扩张合并铜绿假单胞菌感染成人患者的双盲随机安慰剂对照 3 期临床试验。

A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection.

机构信息

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Thoracic Surgery, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Department of Respiratory and Critical Care Medicine, Institute of Respiratory Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

出版信息

Chest. 2023 Jan;163(1):64-76. doi: 10.1016/j.chest.2022.07.007. Epub 2022 Jul 19.

DOI:10.1016/j.chest.2022.07.007

PMID:35863486

Abstract

BACKGROUND

Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection.

RESEARCH QUESTION

Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection?

STUDY DESIGN AND METHODS

This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29.

RESULTS

The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups.

INTERPRETATION

TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection.

TRIAL REGISTRATION

ClinicalTrials.gov; No. NCT03715322; URL: www.

CLINICALTRIALS

gov.

摘要

背景

很少有大规模研究证明妥布霉素雾化在支气管扩张症中的疗效。我们评估了雾化吸入妥布霉素溶液（TIS）在铜绿假单胞菌感染的支气管扩张症成人患者中的疗效和安全性。

研究问题

TIS 是否能有效降低支气管扩张症患者痰液中铜绿假单胞菌密度并改善铜绿假单胞菌感染患者的支气管扩张症特异性生活质量？

研究设计和方法

这是一项为期 16 周的、多中心、随机、双盲、安慰剂对照的 3 期临床试验。符合条件的支气管扩张症成年患者于 2018 年 10 月至 2021 年 7 月招募。在常规治疗的基础上，患者通过振动网孔雾化器雾化吸入 TIS（300mg/5mL，每日 2 次）或生理盐水（5mL，每日 2 次）。治疗包括两个周期，每个周期包括 28 天的治疗期和 28 天的停药期。主要疗效终点包括治疗第 29 天铜绿假单胞菌密度和支气管扩张症呼吸症状生活质量评分与基线相比的变化。

结果

意向治疗人群中，妥布霉素组有 167 例患者，安慰剂组有 172 例患者。与安慰剂相比，TIS 治疗显著降低了铜绿假单胞菌密度（校正平均差值，1.74 log 菌落形成单位/g；95%置信区间，1.12-2.35；P<0.001），并显著改善了支气管扩张症呼吸症状生活质量评分（校正平均差值，7.91；95%置信区间，5.72-10.11；P<0.001），第 29 天。第 85 天也观察到类似的结果。TIS 治疗显著降低了第 29、57 和 85 天的 24 小时痰量和痰脓性评分。与安慰剂组相比，第 29 天妥布霉素组有更多患者的痰液铜绿假单胞菌培养转为阴性（29.3%比 10.6%）。妥布霉素组与安慰剂组不良事件和严重不良事件的发生率相当。