Dushianthan Ahilanandan, Clark Howard, Madsen Jens, Mogg Robin, Matthews Lewis, Berry Lee, de la Serna Jorge Bernardino, Batchelor James, Brealey David, Hussell Tracy, Porter Joanna, Djukanovic Ratko, Feelisch Martin, Postle Anthony, Grocott Michael P W
Respiratory and Critical Care Theme, Southampton NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK.
Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK.
Trials. 2020 Dec 10;21(1):1014. doi: 10.1186/s13063-020-04944-5.
SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure.
This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients.
This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent.
Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician.
The co-primary outcome is the improvement in oxygenation (PaO/FiO ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers.
After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre.
BLINDING (MASKING): This is an open-labelled unblinded study.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control).
Current protocol version is V2 dated 5 of June 2020. The recruitment is currently ongoing and started on the 14 of October 2020. The anticipated study completion date is November 2021.
ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒优先与II型肺泡上皮细胞上的血管紧张素转换酶2（ACE2）结合，引发炎症反应和组织损伤，这可能会损害表面活性剂的合成，导致肺泡塌陷，加重缺氧并导致呼吸衰竭。本研究的目的是评估雾化表面活性剂对因呼吸衰竭需要机械通气的成年COVID-19患者的可行性、安全性和有效性。
本研究是一项针对20名COVID-19患者的剂量递增随机开放标签临床试验。
本研究在两个中心进行：南安普敦大学医院和伦敦大学学院医院。符合条件的参与者年龄≥18岁，因COVID-19住院（经PCR确诊），需要气管插管，并在机械通气24小时内入组。对于无法同意的患者，在入组前需获得个人法定代表人（PerLR）或专业法定代表人（ProfLR）的同意。以下为排除标准：24小时内即将预期死亡；表面活性剂给药的特定禁忌症（如已知过敏、气胸、肺出血）；已知或疑似怀孕；4期慢性肾病或需要透析（即估算肾小球滤过率<30）；肝功能衰竭（Child-Pugh C级）；预计在72小时内转至非研究地点的另一所医院；目前或近期（1个月内）参与另一项研究，据研究者认为，出于安全原因将妨碍入组；以及拒绝同意或同意。
干预措施：本研究基于一种研究性药物/器械组合产品。表面活性剂产品为牛肺表面活性剂（Alveofact®），一种天然动物源性（牛）肺表面活性剂，制成冻干粉末装于108 mg小瓶中，并在预填充注射器提供的缓冲液中复溶至45 mg/mL。它通过肺灌洗分离得到，按重量计是以下成分的混合物：磷脂（75%磷脂酰胆碱、13%磷脂酰甘油、3%磷脂酰乙醇胺、1%磷脂酰肌醇和1%鞘磷脂）、5%胆固醇、1%脂溶性表面活性剂相关蛋白（SP-B和SP-C）、极低水平的游离脂肪酸、溶血磷脂酰胆碱、水和0.3%钙。给药装置为AeroFact-COVID™雾化器，一种基于Aerogen® Solo振动网雾化器的研究性装置。表面活性剂的给药时间和剂量递增计划如下。第1组：3名患者将在0小时、8小时和24小时给药时各接受10瓶（1080 mg）表面活性剂。2名对照不进行安慰剂干预。第2组：3名患者将在0小时和8小时给药时各接受10瓶（1080 mg）表面活性剂，在24小时给药时接受30瓶（3240 mg）。2名对照不进行安慰剂干预。第3组：3名患者将在0小时给药时接受10瓶（1080 mg）表面活性剂，在8小时和24小时给药时各接受30瓶（3240 mg）。2名对照不进行安慰剂干预。第4组：3名患者将在0小时、8小时和24小时给药时各接受30瓶（3240 mg）表面活性剂。加入了2名对照。2名对照不进行安慰剂干预。试验指导委员会将在数据监测委员会的建议下，在每个队列完成后（达到48小时主要结局时间点），根据可用的可行性、不良事件、安全性和有效性数据审查试验进展以及剂量递增/维持/减少情况。试验不会因缺乏疗效而停止。试验可能因安全或可行性问题提前终止。对照：不进行安慰剂干预。所有参与者将按照当地机械通气患者的政策接受常规标准治疗，并由主治医生自行决定所有其他治疗。
共同主要结局是研究开始后48小时氧合改善情况（动脉血氧分压/吸入氧分数值比值）和肺通气情况（通气指数（VI），其中VI = [呼吸频率×（气道峰压 - 呼气末正压）×动脉血二氧化碳分压]/1000）。次要结局包括不良事件（AE）、器械不良事件（ADE）、严重不良事件（SAE）和严重器械不良事件（SADE）的发生频率和严重程度、肺顺应性变化、研究开始后24小时和48小时通气支持的呼气末正压（PEEP）需求变化、根据世界卫生组织主方案（2020年）中描述的序贯量表在住院期间记录的达到一个改善点的时间所定义的临床改善情况、机械通气天数、第21天无机械通气天数（VFD）、重症监护病房住院时长、住院天数以及第28天死亡率。探索性终点将包括使用PCR对气管吸出物中的SARS-CoV-2病毒载量进行定量、对深部气管吸出物样本（DTAS）的表面活性剂动力学（合成和周转）及功能（表面张力降低）进行评估、血浆和DTAS中的表面活性剂磷脂浓度、血浆和DTAS中的炎症标志物（细胞和细胞因子）以及血液氧化应激标志物。
在获得知情同意后，符合纳入标准的患者将使用基于互联网的区组随机化服务（用于临床试验的ALEA工具，FormsVision BV）结合电子数据收集，按3:2随机分配至治疗组和对照组。随机化将由招募中心进行，并为该中心分配一个唯一的受试者标识符。
设盲（遮蔽）：这是一项开放标签的非设盲研究。
随机化数量（样本量）：总样本量为20名COVID-19机械通气患者（12名干预组；8名对照组）。
当前方案版本为2020年6月5日的V2版。目前正在招募患者，于2020年10月14日开始。预计研究完成日期为2021年11月。
ClinicalTrials.gov：NCT04362059（2020年4月24日注册），EUDAMED编号：CIV-GB-20-06-033328, EudraCT编号：2020-001886-35（2020年5月11日注册）完整方案：完整方案作为附加文件附上，并可从试验网站获取（附加文件1）。为了加快此材料传播，已去除了常见格式；本信函作为完整方案关键要素的总结。本研究方案已按照标准方案项目：临床干预试验建议（SPIRIT）指南进行报告（附加文件2）。
