Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by , and spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with , , and is complete. Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference −1·1% [95% CI −14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI −9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Cidara Therapeutics and Mundipharma.

中文翻译：

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雷扎芬净与卡泊芬净治疗念珠菌血症和侵袭性念珠菌病 (ReSTORE)：一项多中心、双盲、双模拟、随机 3 期试验

Rezafungin 是一种下一代、每周一次的棘白菌素，正在开发中，用于治疗念珠菌血症和侵袭性念珠菌病，以及预防血液和骨髓移植后由 、 和 spp 引起的侵袭性真菌病。我们的目的是比较静脉注射雷扎芬净与静脉注射卡泊芬净治疗念珠菌血症和侵袭性念珠菌病的疗效和安全性。ReSTORE 是一项多中心、双盲、双模拟、随机 3 期试验，在 15 个国家的 66 个三级护理中心进行。患有全身症状且真菌学证实为念珠菌血症或侵袭性念珠菌病的成人（≥18岁）符合纳入条件，并随机分配（1:1）接受每周一次静脉注射雷扎芬净（第 1 周 400 mg，随后每周 200 mg，持续总共 2 至 4 剂）或静脉注射卡泊芬净（第 1 天 70 mg 负荷剂量，随后每天 50 mg），持续不超过 4 周。欧洲医疗机构 (EMA) 的主要终点是第 14 天的总体治愈率（包括临床治愈、放射学治愈和真菌学根除），美国食品和药物管理局 (FDA) 的主要终点是 30 天全因死亡率，两者均是目标非劣效裕度为 20%，在修改后的意向治疗人群中进行评估（接受一剂或多剂研究药物的所有患者，并根据血液或其他正常无菌部位的培养物记录感染情况）随机化前 96 小时）。安全性通过安全人群中不良事件和死亡的发生率和类型进行评估，安全人群定义为接受任何剂量研究药物的所有患者。试验已在 、 、 注册，并已完成。2018年10月12日至2021年8月29日期间，对222名患者进行了纳入筛选，其中199名患者（118名[59%]男性；81名[41%]女性；平均年龄61岁[SD 15·2]）被随机分组分配（100 [50%] 患者分配至雷扎芬净组，99 [50%] 患者分配至卡泊芬净组）。雷扎芬净组 93 名患者中的 55 名 (59%) 和卡泊芬净组 94 名患者中的 57 名 (61%) 在第 14 天实现全面治愈（加权治疗差异 -1·1% [95% CI -14·9 至12·7]；EMA 主要终点）。瑞扎芬净组 93 名患者中的 22 名患者 (24%) 和卡泊芬净组 94 名患者中的 20 名患者 (21%) 在第 30 天死亡或生存状态未知（治疗差异 2·4% [95% CI -9·7至14·4]；FDA 主要终点）。在安全性分析中，雷扎芬净组 98 名患者中的 89 名患者（91%）和卡泊芬净组 98 名患者中 83 名患者（85%）出现至少一种治疗引起的不良事件。两组中至少有 5% 的患者发生的最常见的治疗相关不良事件是发热、低钾血症、肺炎、感染性休克和贫血。雷扎芬净组中有 55 名患者（56%）和卡泊芬净组有 52 名患者（53%）出现严重不良事件。我们的数据显示，在第 14 天总体治愈率 (EMA) 和 30 天全因死亡率 (FDA) 的主要终点方面，雷扎芬净不劣于卡泊芬净。治疗最初几天的疗效值得评估。治疗中出现的或严重的不良事件没有令人担忧的趋势。这些 3 期结果显示了 rezafungin 的有效性和安全性，并支持其持续开发。Cidara Therapeutics 和 Mundipharma。