Abstract：
Astodrimer sodium is a dendrimer molecule with antiviral and virucidal activity against SARS-CoV-2 and other respiratory viruses in vitro, and has previously been shown to be safe and well tolerated, and not systemically absorbed, when applied to the vaginal mucosa. To investigate its potential utility as a topical antiviral, astodrimer sodium has been reformulated for application to the nasal mucosa to help reduce viral load before or after exposure to respiratory infection. The current investigation assessed the safety, tolerability and absorption of astodrimer sodium 1% antiviral nasal spray. This was a single-centre, double-blinded, randomized, placebo-controlled, exploratory clinical investigation. Forty healthy volunteers aged 18 to 65 years with no clinically significant nasal cavity examination findings were randomized 3:1 to astodrimer sodium nasal spray (N = 30) or placebo (N = 10) at an Australian clinical trials facility. An initial cohort of participants (N = 12 astodrimer, N = 4 placebo) received a single application (one spray per nostril) to assess any acute effects, followed by a washout period, before self-administering the spray four times daily for 14 days to represent an intensive application schedule. Extent of absorption of astodrimer sodium via the nasal mucosa was also assessed in this cohort. A second cohort of participants (N = 18 astodrimer, N = 6 placebo) self-administered the spray four times daily for 14 days. The primary endpoint was safety, measured by frequency and severity of treatment emergent adverse events (TEAEs), including clinically significant nasal cavity examination findings, in the safety population (all participants randomized who administered any spray). Participants were randomized between 6 January 2021 and 29 March 2021. TEAEs occurred in 8/10 (80%) participants in the placebo arm and 19/30 (63.3%) participants in the astodrimer sodium arm; all were of mild intensity. TEAEs considered potentially related to study product occurred in 5/10 (50%) participants receiving placebo and 10/30 (33.3%) of participants receiving astodrimer sodium. No participants experienced serious AEs, or TEAEs leading to withdrawal from the study. No systemic absorption of astodrimer sodium via the nasal mucosa was detected. Astodrimer sodium nasal spray was well tolerated and is a promising innovation warranting further investigation for nasal administration to potentially reduce infection and spread of community acquired respiratory virus infections.Trial Registration: ACTRN12620001371987, first registered 22-12-2020 (Australia New Zealand Clinical Trials Registry, https://anzctr.org.au/ ).
摘要：
Astodrimer钠是一种树枝状分子，在体外对SARS-CoV-2和其他呼吸道病毒具有抗病毒和杀病毒活性，以前被证明是安全的，耐受性良好，而不是系统吸收，当应用于阴道粘膜时。为了研究其作为局部抗病毒的潜在效用，在暴露于呼吸道感染之前或之后，已将钠重新配制用于鼻粘膜，以帮助减少病毒载量。目前的调查评估了安全性，1%抗病毒鼻喷雾剂的耐受力和吸收。这是一个单一的中心，双盲,随机化，安慰剂对照,探索性临床调查。在澳大利亚的临床试验机构中，将40名年龄在18至65岁之间，没有临床上显着的鼻腔检查结果的健康志愿者随机分为3：1，分别接受阿托德默钠鼻喷雾剂（N=30）或安慰剂（N=10）。最初的一组参与者(N=12，N=4安慰剂）接受单次应用（每个鼻孔一次喷雾）以评估任何急性影响，接下来是一个冲洗期，在自我施用喷雾剂之前，每天四次，共14天，以代表密集的应用时间表。在该队列中还评估了通过鼻粘膜吸收钠的程度。第二组参与者(N=18岁，N=6安慰剂）每天四次自我施用喷雾剂，共14天。主要终点是安全性，通过治疗紧急不良事件(TEAE)的频率和严重程度来衡量，包括有临床意义的鼻腔检查结果，在安全性人群中（所有接受任何喷雾剂的参与者）。参与者在2021年1月6日至2021年3月29日之间进行随机分组。TEAE发生在安慰剂组的8/10（80％）参与者和钠钠组的19/30（63.3％）参与者中;都是轻度的。被认为与研究产品潜在相关的TEAE发生在5/10（50％）接受安慰剂的参与者和10/30（33.3％）接受钠的参与者中。没有参与者经历严重的AE，或TEAE导致退出研究。未检测到通过鼻粘膜的钠的全身吸收。Astodrimer钠鼻喷雾剂具有良好的耐受性，是一项有前途的创新，需要对鼻腔给药进行进一步研究，以可能减少社区获得性呼吸道病毒感染的感染和传播。试验注册：ACTRN12620001371987，首次注册22-12-2020（澳大利亚新西兰临床试验注册，https://anzctr.org。au/).
