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

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A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection
Chest ( IF 9.6 ) Pub Date : 2022-07-19 , DOI: 10.1016/j.chest.2022.07.007
Wei-Jie Guan ₁ , Jin-Fu Xu ₂ , Hong Luo ₃ , Xing-Xiang Xu ₄ , Yuan-Lin Song ₅ , Wan-Li Ma ₆ , Zong-An Liang ₇ , Xue-Dong Liu ₈ , Guo-Jun Zhang ₉ , Xiao-Ju Zhang ₁₀ , Rong-Kai Li ₁₁ , Shu-Yang Zhu ₁₂ , Yi-Jie Zhang ₁₃ , Xing-Jun Cai ₁₄ , Li-Ping Wei ₁₅ , Dong-Bo Tian ₁₆ , Hui Zhao ₁₇ , Ping-Yan Chen ₁₈ , Jie-Ming Qu ₁₉ , Nan-Shan Zhong ₂₀ ,

Affiliation

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.
Department of Pulmonary and Critical Care Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Subei People's Hospital, Suzhou, Jiangsu, China.
Zhongshan Hospital, Fudan University, Shanghai, China.
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Affiliated West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Tsingtao Municipal Hospital, Qingdao, Shandong, China.
Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Xinxiang First People's Hospital, Xinxiang, Henan, China.
Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Affiliated Huaihe Hospital of Henan University, Huaihe, Henan, China.
Hainan General Hospital, Haikou, Hainan, China.
Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Qingyuan People's Hospital, Qingyuan, Guangdong, China.
Second Affiliated Hospital of Anhui Medical University, Anhui, China.
State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University.
Affiliated Ruijin Hospital, School of Medicine, Shanghai Jiaotong University.
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.

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 log₁₀ 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

中文翻译：

妥布霉素吸入溶液治疗铜绿假单胞菌感染支气管扩张症成人的双盲随机安慰剂对照 3 期试验

背景

很少有大规模研究证明妥布霉素雾化治疗支气管扩张的疗效。我们评估了雾化妥布霉素吸入溶液 (TIS) 在成人支气管扩张伴铜绿假单胞菌感染中的疗效和安全性。

研究问题

TIS能否有效降低痰液铜绿假单胞菌浓度，改善支气管扩张伴铜绿假单胞菌感染患者的支气管扩张特异性生活质量？

研究设计和方法

这是一项为期 16 周的 3 期多中心、随机、双盲、安慰剂对照试验。从2018年10月至2021年7月招募了符合条件的患有支气管扩张症的成人。在常规护理的基础上，患者通过振网雾化器雾化TIS（300 mg / 5 mL，每天两次）或生理盐水（5 mL，每天两次）。治疗包括两个周期，每个周期包括 28 天治疗和 28 天停止治疗。共同主要终点包括第 29 天铜绿假单胞菌密度和生活质量支气管扩张呼吸道症状评分相对于基线的变化。

结果

改良意向治疗人群包括妥布霉素组 167 名患者和安慰剂组 172 名患者。与安慰剂相比，TIS 导致铜绿假单胞菌密度显着降低（调整后的平均差，1.74 log ₁₀菌落形成单位/g；95% CI，1.12-2.35；P < .001），并且质量改善更大- 第 29 天的生命支气管扩张呼吸系统症状评分（调整后的平均差异，7.91；95% CI，5.72-10.11；P < .001）。在第 85 天观察到类似的结果。TIS 导致 24 小时痰量显着减少和第 29、57 和 85 天的痰液化脓评分。更多患者的铜绿假单胞菌培养呈阴性在第 29 天，妥布霉素组比安慰剂组高（29.3% 对 10.6%）。两组不良事件和严重不良事件的发生率具有可比性。