METHODS: In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population.
RESULTS: A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported.
CONCLUSIONS: Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis. Clinical Trials Registration.NCT04160468.
方法:在混乱中,优势设计第三阶段研究,金黄色葡萄球菌菌血症/心内膜炎患者被随机分组,除了接受标准治疗抗生素外,还接受单剂量的静脉外,还接受1次静脉给药或安慰剂.主要疗效结果是MRSA人群在第14天的临床反应。
结果:根据非盲数据安全监测委员会的建议,在研究因无效而停止之前,共259名患者被随机分组。MRSA人群(n=97)在第14天时的临床反应率为50.0%(抗细菌酶+抗生素;32/64)与60.6%(单独使用抗生素;20/33)(P=0.392)。总的来说,各组的不良事件发生率相似.未报告与解异菌酶相关的超敏反应的不良事件。
结论:Exebacase+抗生素未能在第14天改善MRSA菌血症/心内膜炎患者的临床反应。根据2期数据,该结果是出乎意料的,该数据建立了MRSA菌血症/心内膜炎患者的解癌酶抗生素的概念验证。在单独抗生素组中,临床缓解率高于2期。研究人群中的异质性和2期或3期研究中相对较小的样本量可能增加了第14天临床结果的多个组成部分的不平衡的可能性。本研究为金黄色葡萄球菌菌血症/心内膜炎的未来优势研究提供了借鉴。