脂质体阿米卡星吸入治疗非结核分枝杆菌肺病的随机试验
Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease.
作者信息
Olivier Kenneth N, Griffith David E, Eagle Gina, McGinnis John P, Micioni Liza, Liu Keith, Daley Charles L, Winthrop Kevin L, Ruoss Stephen, Addrizzo-Harris Doreen J, Flume Patrick A, Dorgan Daniel, Salathe Matthias, Brown-Elliott Barbara A, Gupta Renu, Wallace Richard J
机构信息
1 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
2 The University of Texas Health Science Center at Tyler, Tyler, Texas.
出版信息
Am J Respir Crit Care Med. 2017 Mar 15;195(6):814-823. doi: 10.1164/rccm.201604-0700OC.
RATIONALE
Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease.
OBJECTIVES
In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease.
METHODS
During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events.
MEASUREMENTS AND MAIN RESULTS
The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation.
CONCLUSIONS
Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).
理论依据
冗长、多药联用、有毒且低效的治疗方案限制了非结核分枝杆菌肺病的治疗。
目的
在这项II期研究中，我们调查了吸入用脂质体阿米卡星（LAI）治疗难治性非结核分枝杆菌肺病（鸟分枝杆菌复合群[MAC]或脓肿分枝杆菌）的疗效和安全性。
方法
在双盲阶段，患者被随机分配接受LAI（590毫克）或安慰剂，每日一次，加入其多药治疗方案，持续84天。两组均可再接受84天的开放标签LAI治疗。主要终点是从基线到第84天在半定量分枝杆菌生长量表上的变化。其他终点包括痰菌转阴、6分钟步行距离和不良事件。
测量指标和主要结果
改良意向性治疗人群包括89名患者（LAI组=44名；安慰剂组=45名）。样本的平均年龄为59岁；88%为女性；92%为白人；80名和59名患者分别在双盲阶段和开放标签阶段完成了研究药物给药。未达到主要终点（P=0.072）；然而，在第84天，LAI组中更多患者的痰培养至少有一次转阴（44名患者中的14名[32%] vs. 45名患者中的4名[9%]；P=0.006），且6分钟步行试验有所改善（+20.6米 vs. -25.0米；P=0.017）。治疗效果主要在无囊性纤维化的MAC患者中观察到，且在LAI治疗1年后仍持续存在。大多数不良事件为呼吸道事件，在一些患者中导致停药。
结论
虽然未达到主要终点，但在难治性MAC肺病患者中，在多药治疗方案中加入LAI与安慰剂相比，在痰菌转阴和6分钟步行距离方面有所改善，且全身毒性有限。该领域需要进一步研究。临床试验已在www.clinicaltrials.gov注册（NCT01315236）。
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