Cunnion Kenji, Goss Jessica, Hair Pamela, Dell Linda, Roberson Destrey, Thienel Ulrich, Müller Meike, Carstensen-Aurèche Saskia, Badorrek Philipp, Holz Olaf, Hohlfeld Jens M
Department of Research and Medical Affairs, ReAlta Life Sciences, Norfolk, VA, USA.
Children's Hospital of The King's Daughters, Norfolk, VA, USA.
ERJ Open Res. 2024 Sep 16;10(4). doi: 10.1183/23120541.01006-2023. eCollection 2024 Jul.
This study was a randomised, double-blind, placebo-controlled study intended to establish the translatability of the RLS-0071 mechanisms of action from animal disease models to humans by inhibiting neutrophil-mediated inflammation at the tissue level and major inflammatory biomarkers. We hypothesised that RLS-0071 inhibits a temporary neutrophil-mediated inflammation in the lungs induced by inhalation of low-dose lipopolysaccharide (LPS) in healthy participants.
Participants were randomised to one of three arms to receive inhaled LPS followed by three doses of either low-dose (10 mg·kg) or high-dose (120 mg·kg loading dose followed by two doses of 40 mg·kg) RLS-0071 or placebo (saline) every 8 h. Biomarkers evaluating inflammatory responses, with absolute neutrophil counts in induced sputum as the primary end-point, were collected before and at 6 and 24 h after LPS challenge.
Active treatment with RLS-0071 showed a similar safety profile to participants receiving placebo. RLS-0071 significantly decreased the numbers of neutrophils in sputum at 6 h post LPS by approximately half (p=0.04). Neutrophil effectors myeloperoxidase, neutrophil elastase and interleukin-1β in sputum were also significantly decreased at 6 h for RLS-0071 compared with placebo. Several biomarkers showed trends suggesting sustained decreases for RLS-0071 placebo at 24 h.
This clinical trial demonstrated that RLS-0071 was safe and well tolerated and modulated neutrophil-mediated inflammation in humans after inhaled LPS challenge, consistent with results from prior animal model studies.
本研究是一项随机、双盲、安慰剂对照研究，旨在通过在组织水平和主要炎症生物标志物上抑制中性粒细胞介导的炎症，确定RLS-0071作用机制从动物疾病模型到人类的可转化性。我们假设RLS-0071可抑制健康参与者吸入低剂量脂多糖（LPS）后在肺部引发的暂时性中性粒细胞介导的炎症。
参与者被随机分为三组之一，吸入LPS后，每8小时接受三剂低剂量（10mg·kg）或高剂量（120mg·kg负荷剂量，随后两剂40mg·kg）的RLS-0071或安慰剂（生理盐水）。在LPS激发前以及激发后6小时和24小时收集评估炎症反应的生物标志物，以诱导痰中的绝对中性粒细胞计数作为主要终点。
RLS-0071的积极治疗显示出与接受安慰剂的参与者相似的安全性。RLS-0071在LPS激发后6小时显著降低了痰液中的中性粒细胞数量，降幅约为一半（p = 0.04）。与安慰剂相比，RLS-0071在6小时时还显著降低了痰液中的中性粒细胞效应物髓过氧化物酶、中性粒细胞弹性蛋白酶和白细胞介素-1β。几种生物标志物显示出趋势，表明RLS-0071在24小时时比安慰剂持续下降。
这项临床试验表明，RLS-0071安全且耐受性良好，并在吸入LPS激发后调节了人类中性粒细胞介导的炎症，这与先前动物模型研究的结果一致。
