There remains an unmet need to address the substantial morbidity and mortality associated with severe community-acquired pneumonia (sCAP). Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse animal models of infectious and noninfectious inflammation. This blinded dose-escalation safety study involved non-intensive care unit (ICU) patients admitted for mild CAP and randomized 3:1 to receive adjunctive rhu-pGSN or placebo intravenously. Thirty-three subjects were treated: 8 in the single-dose phase and 25 in the multidose phase. For the single-dose phase, rhu-pGSN at 6 mg/kg of body weight was administered once. For the multidose phase, a daily rhu-pGSN dose of 6, 12, or 24 mg/kg was given on 3 consecutive days. Adverse events (AEs) were generally mild in both treatment groups irrespective of dose. The only serious AE (SAE) in the single-dose phase was a non-drug-related pneumonia in a rhu-pGSN recipient who died after institution of comfort care. One single-dose placebo recipient had a drug-related AE (maculo-papular rash). In the multidose phase, there were 2 SAEs in 1 placebo recipient, including a fatal pulmonary embolism. In the 18 rhu-pGSN recipients in the multidose phase, there were no serious or drug-related AEs, and nausea and increased blood pressure were each reported in 2 patients. The median rhu-pGSN half-life exceeded 17 h with all dosing regimens, and supraphysiologic levels were maintained throughout the 24-h dosing interval in the 2 highest dosing arms. Rhu-pGSN was well tolerated overall in CAP patients admitted to non-ICU beds, justifying a larger proof-of-concept trial in an ICU population admitted with sCAP. (This study has been registered at ClinicalTrials.gov under identifier NCT03466073.)

中文翻译：

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非严重社区获得性肺炎住院患者重组人血浆凝溶胶蛋白的安全性和药代动力学。

解决与严重的社区获得性肺炎（sCAP）相关的高发病率和高死亡率的需求仍未得到满足。重组人血浆凝溶胶蛋白（rhu-pGSN）改善了感染性和非感染性炎症的多种动物模型中的疾病结果。这项盲目的剂量递增安全性研究涉及接受轻度CAP的非重症监护病房（ICU）患者，并以3：1的比例随机接受静脉注射辅助性rhu-pGSN或安慰剂。对33名受试者进行了治疗：单剂量阶段为8名，多剂量阶段为25名。对于单剂量阶段，一次以6 mg / kg体重施用rhu-pGSN。对于多剂量阶段，连续3天每天给予6、12或24 mg / kg的rhu-pGSN剂量。无论剂量如何，两个治疗组的不良事件（AEs）一般较轻。在单剂量阶段，唯一的严重AE（SAE）是在接受安慰护理后死亡的rhu-pGSN接受者中与药物无关的肺炎。一位单剂量安慰剂接受者患有药物相关的AE（巨丘疹）。在多剂量阶段，有1位安慰剂接受者发生2次SAE，包括致命的肺栓塞。在多剂量阶段的18位rhu-pGSN接受者中，没有严重或与药物相关的AE，并且2例患者分别报告有恶心和血压升高。在所有给药方案中，rhu-pGSN的中位半衰期均超过了17小时，并且在2个最高给药组的整个24小时给药间隔中维持了超生理水平。Rhu-pGSN在接受非ICU病床的CAP患者中总体耐受性良好，这证明了在接受sCAP的ICU人群中进行的更大的概念验证试验是合理的。