University Hospital Galway, Newcastle Road, Galway, Ireland.
National University of Ireland Galway, Galway, Ireland.
Trials. 2022 Sep 14;23(1):774. doi: 10.1186/s13063-022-06518-z.
COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia.
This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP.
This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.
ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.
COVID-19 肺炎与急性呼吸窘迫综合征（ARDS）的发展有关，表现出一些典型的组织学特征。这些特征包括弥漫性肺泡损伤和广泛的肺凝血激活。这导致微脉管系统中的纤维蛋白沉积，导致气囊中的透明膜形成。精心设计的临床试验发现，雾化肝素可限制肺纤维蛋白沉积，减轻 ARDS 的进展，加速恢复，并且在非 COVID-19 ARDS 中是安全的。未分级肝素还可使 SARS-CoV-2 病毒失活并阻止其进入哺乳动物细胞。因此，雾化肝素可能会限制纤维蛋白介导的肺损伤并抑制 SARS-CoV-2 的肺部感染。基于这些发现，我们设计了 CHARTER-Ireland 研究，这是一项在需要高级呼吸支持的 COVID-19 肺炎患者中进行雾化肝素的 1b/2a 期随机对照研究。
这是一项多中心、1b/2a 期、随机、平行组、开放标签研究。该研究将随机招募 40 名接受重症监护区高级呼吸支持的 SARS-CoV-2 阳性患者。通过 1:1 分配，将他们随机分为接受常规护理加每日 6 小时雾化未分级肝素至第 10 天的常规护理加雾化未分级肝素组，或仅接受常规护理组。该研究旨在评估未分级肝素是否会降低与 ARDS 相关的促凝反应，直至第 10 天。该研究还将评估雾化肝素的安全性和耐受性，定义为严重不良事件的数量；分别为气管插管和非气管插管患者的氧指数和呼吸氧合指数；通气比；以及白细胞介素（IL）-1β、IL6、IL-8、IL-10 和可溶性肿瘤坏死因子受体 1、C 反应蛋白、降钙素原、铁蛋白、纤维蛋白原和乳酸脱氢酶的血浆浓度，以及 IL-1β/IL-10 和 IL-6/IL-10 的比值。这些参数将在第 1、3、5 和 10 天进行评估；从高级呼吸支持中分离出来的时间、从重症监护病房出院的时间和第 28 天进行气管切开的时间；以及第 28 天和第 60 天以及出院时的存活率，以第 60 天为截止日期。我们研究的一些临床结果数据将包含在国际荟萃分析、CHARTER 和 INHALE-HEP 中。
该试验旨在提供潜在治疗益处的证据，同时确定 SARS-CoV-2 感染相关 ARDS 中雾化肝素的安全性。
ClinicalTrials.gov NCT04511923。于 2020 年 8 月 13 日注册。方案版本 8，2021 年 12 月 22 日。方案标识符：NUIG-2020-003。EudraCT 注册号：2020-003349-12。2020 年 10 月 9 日。
