协议:多中心、无缝、第二阶段自适应随机平台研究评估多个候选药物的有效性和安全性COVID-19住院患者的治疗:一个结构化的总结为随机对照试验研究协议。

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威尔金森T, Dixon R,页面C,卡罗尔M,格里菲斯G,何鸿燊LP De Soyza,费尔顿T,刘易斯KE, Phekoo K,查尔默斯JD,戈登,McGarvey L, Doherty J,读RC, Shankar-Hari M, Martinez-Alier N,凯利M,邓肯•G墙R,赛克斯J,辛格萨默斯C, D

试验。2020年7月31日,21 (1):691。doi: 10.1186 / s13063 - 020 - 04584 - 9。

PubMed ID

32736596 (在PubMed

]

文摘

目的:阶段1:评估候选药物的安全性和有效性的附加治疗标准护理(SoC)在患者住院COVID-19筛选阶段。阶段2:确认候选代理人选择的有效性证据的基础上,从第一阶段患者住院COVID-19扩张阶段。试验设计:协议是一个无缝的,第二阶段,自适应,随机对照研究平台,旨在快速测试COVID-19的候选药物治疗。与每个候选人代理被设计为一个主协议包括通过自己的订阅”协议,最初每个候选人之间随机试验同样和一个同时代的SoC手臂(可以调整成2:1)。候选人目前代理包括bemcentinib MEDI3506、acalabrutinib zilucoplan nebulised肝素。对于每个候选人共有60名患者将在第一阶段招募。如果第一阶段提供的证据效力和可接受的安全性的候选人将进入第二阶段,共有大约126名患者将招募到每个研究手臂订阅”协议。新生和结果不会跨阶段共享;端点、分析和样本大小以证据为基础的第二阶段可能调整从阶段1。额外的武器可能被添加为新的潜在候选人通过候选人代理具体sub-protocols代理确认。 PARTICIPANTS: The study will include hospitalised adult patients (>/=18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22(nd) April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95 , registered 28(th) April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
Acalabrutinib	酪氨酸受体激酶BTK	蛋白质	人类	是的	抑制剂	细节
Bemcentinib	斯派克糖蛋白	蛋白质	SARS-CoV-2	是的	抑制剂	细节
MEDI3506	Interleukin-33	蛋白质	人类	未知的	抗体监管机构	细节
Zilucoplan	补充C5	蛋白质	人类	未知的	抑制剂	细节