Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial
Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) Trial
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DOI：
10.1093/cid/ciz090
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发表时间：
2019-12-01
影响因子：
11.8
通讯作者：
Gasink, Leanne B.
中科院分区：
文献类型：
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作者：
File, Thomas M., Jr.;Goldberg, Lisa;Gasink, Leanne B.
背景左法莫林是一种截短侧耳素抗生素，对通常引起社区获得性细菌性肺炎（CABP）的病原体有活性。LEAP 1研究是一项全球性的非劣效性试验，旨在评价来法莫林治疗CABP的有效性和安全性。在这项双盲研究中，肺炎结局研究小组风险等级>= III的CABP成人以1：1的比例随机接受150 mg静脉注射（IV）每12小时一次的来法莫林或400 mg静脉注射每24小时一次的阿氟沙星。6次给药后，如果符合预先规定的改善标准，则患者可以转换为口服研究药物。如果怀疑存在耐甲氧西林金黄色葡萄球菌，则分别将利奈唑胺或安慰剂添加至利福沙星或来福莫林中。美国食品药品监督管理局的主要终点是意向治疗（ITT）人群中研究药物首次给药后96 24小时的早期临床应答（ECR）（非劣效性界值，12.5%）。欧洲药品管理局的共同主要终点是在改良ITT（mITT）和临床可评价（CE）人群中研究药物末次给药后5-10天研究者对临床应答（IACR）的评估（非劣效性界值，10%）。共有551例患者接受随机化（n = 276例来法莫林; n = 275例阿氟沙星）。左法莫林的ECR非劣效于阿氟沙星（分别为87.3%和90.2%;差异-2.9%，95%置信区间[CI] g-8.5至2.8）和IACR（mITT，分别为81.7%和84.2%;差异-2.6%，95%CI-8.9至3.9; CE，分别为86.9%和89.4%;差异-2.5%，95%CI-8.4至3.4）。因治疗后出现的不良事件而停用研究药物的发生率，来法莫林组为2.9%，利福那星组为4.4%。在主要疗效终点方面，左法莫林非劣效于阿氟沙星，总体安全且耐受性良好。
Background. Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP.Methods. In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class >= III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%).Results. There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.Conclusions. Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated.