Michael W Dunne, Steven I Aronin, Anita F Das, Karthik Akinapelli, Jeanne Breen, Michael T Zelasky, Sailaja Puttagunta
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The primary (FDA-specified) endpoint was clinical response at Day 28 [Test-of-Cure (TOC)] in the micro-Modified Intent to Treat (micro-MITT) population.</p><p><strong>Results: </strong>674 patients were randomized. The two treatment arms were well-balanced. E. coli (395 patients) and B. fragilis (111 patients) were the most frequently isolated pathogens. Clinical success rates in the micro-MITT population were 81.9% (204/249) for sulopenem-treated patients and 87.9% (233/265) for ertapenem-treated patients. The lower bound of the confidence interval (CI) for the treatment difference of the primary endpoint was below the prespecified non-inferiority margin of -10.0 [treatment difference -6.0%, 95% CI [-12.2, 0.2]. In all other analysis populations, the lower limit of the 95% CI was above -10.0. Treatment emergent adverse events (all, 26.0% [87/335] vs 23.4% [78/333]; related, 6.0% [20/335] vs 5.1% [17/333]) were similar for sulopenem and ertapenem, respectively. Most events were mild to moderate in severity. There were more serious adverse events in the sulopenem arm (7.5% [25/335] vs 3.6% [12/333]), only two of which were considered possibly drug-related.</p><p><strong>Conclusions: </strong>Sulopenem IV followed by oral sulopenem etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down in treating cIAI in the micro-MITT population. This finding should be interpreted in the context of country regulations, as endpoint timing, primary analysis population and noninferiority margin may vary regionally. 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引用次数: 0
摘要
目的证明在成人复杂性腹腔内感染(cIAI)患者中,静脉注射(IV)舒洛培南与静脉注射厄他培南,然后分别口服治疗方案的非劣效性。方法:住院的成人腹腔内感染患者被随机分为两种治疗方案:静脉注射舒洛培南 5 天后口服舒洛培南依他沙星/丙磺舒,每日两次;或静脉注射厄他培南 5 天后口服环丙沙星/甲硝唑或阿莫西林-克拉维酸(视病原体的基础敏感性而定)。目标治疗时间为 7-10 天。主要(FDA规定的)终点是微型修正治疗意向(micro-MITT)人群第28天的临床反应[治愈试验(TOC)]:结果:674 名患者接受了随机治疗。结果:674 名患者接受了随机治疗。大肠杆菌(395 例)和脆弱拟杆菌(111 例)是最常见的病原体。在 micro-MITT 群体中,舒洛培南治疗患者的临床成功率为 81.9%(204/249),厄他培南治疗患者的临床成功率为 87.9%(233/265)。主要终点治疗差异的置信区间(CI)下限低于预设的非劣效边际-10.0[治疗差异-6.0%,95% CI [-12.2,0.2]]。在所有其他分析人群中,95% CI 的下限高于-10.0。舒洛培南和厄他培南的治疗突发不良事件(全部,26.0% [87/335] vs 23.4% [78/333];相关,6.0% [20/335] vs 5.1% [17/333])分别相似。大多数事件的严重程度为轻度至中度。舒洛培南治疗组发生的严重不良事件较多(7.5% [25/335] vs 3.6% [12/333]),其中只有两例被认为可能与药物有关:结论:在micro-MITT人群中,先静脉注射舒洛培南,再口服舒洛培南依沙氨嘧啶/丙磺舒的治疗效果并不优于先口服厄他培南,再口服降压药的治疗效果。由于终点时间、主要分析人群和非劣效性边际可能因地区而异,因此应根据国家法规来解释这一发现。静脉注射和口服舒洛培南的耐受性都很好;口服制剂允许耐药病原体患者放弃静脉注射治疗:临床试验注册:NCT03358576。
A phase 3 randomized trial of sulopenem vs. ertapenem in patients with complicated intraabdominal infections.
Objective: To demonstrate the noninferiority of intravenous (IV) sulopenem to IV ertapenem, each followed by an oral regimen, in adults with complicated intraabdominal infections (cIAI).
Methods: Hospitalized adults with cIAI were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid twice daily or 5 days of IV ertapenem followed by oral ciprofloxacin/metronidazole or amoxicillin-clavulanate depending on baseline pathogen susceptibility. The target treatment duration was 7-10 days. The primary (FDA-specified) endpoint was clinical response at Day 28 [Test-of-Cure (TOC)] in the micro-Modified Intent to Treat (micro-MITT) population.
Results: 674 patients were randomized. The two treatment arms were well-balanced. E. coli (395 patients) and B. fragilis (111 patients) were the most frequently isolated pathogens. Clinical success rates in the micro-MITT population were 81.9% (204/249) for sulopenem-treated patients and 87.9% (233/265) for ertapenem-treated patients. The lower bound of the confidence interval (CI) for the treatment difference of the primary endpoint was below the prespecified non-inferiority margin of -10.0 [treatment difference -6.0%, 95% CI [-12.2, 0.2]. In all other analysis populations, the lower limit of the 95% CI was above -10.0. Treatment emergent adverse events (all, 26.0% [87/335] vs 23.4% [78/333]; related, 6.0% [20/335] vs 5.1% [17/333]) were similar for sulopenem and ertapenem, respectively. Most events were mild to moderate in severity. There were more serious adverse events in the sulopenem arm (7.5% [25/335] vs 3.6% [12/333]), only two of which were considered possibly drug-related.
Conclusions: Sulopenem IV followed by oral sulopenem etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down in treating cIAI in the micro-MITT population. This finding should be interpreted in the context of country regulations, as endpoint timing, primary analysis population and noninferiority margin may vary regionally. Both IV and oral sulopenem were well-tolerated; the oral formulation allowed patients with resistant pathogens to step down from IV therapy.
期刊介绍:
Clinical Microbiology and Infection (CMI) is a monthly journal published by the European Society of Clinical Microbiology and Infectious Diseases. It focuses on peer-reviewed papers covering basic and applied research in microbiology, infectious diseases, virology, parasitology, immunology, and epidemiology as they relate to therapy and diagnostics.