CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Clin Trials. 2022 Feb;19(1):52-61. doi: 10.1177/17407745211049829. Epub 2021 Oct 10.
BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed.
Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19.
As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites.
Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.
背景/目的：迫切需要安全有效的 COVID-19 疗法。为了满足这一需求，加速 COVID-19 治疗干预和疫苗公私合作伙伴关系启动了 COVID-19 住院患者治疗方案。COVID-19 住院患者治疗方案是一个多臂、多阶段平台主方案，它促进了对住院 COVID-19 成人患者使用新型候选抗病毒治疗药物的安全性和疗效的快速评估。迄今为止，已有五种药物进入该方案，其中三种药物已迅速提供答案。预计 2021 年全年还会有其他药物进入该方案。该方案包含了一些关键的设计和实施特点，以及方案团队面临的挑战，这些特点和挑战都将被呈现并讨论。
三个临床试验网络，包括一个全球临床站点网络，参与了方案的制定和实施。COVID-19 住院患者治疗方案采用多臂、多阶段设计，在入组 300 名患者时采用灵活且强大的无效性和安全性评估方法，随后扩大至全样本量，并在药物显示可接受的安全性和疗效证据时扩大目标人群。通过共享安慰剂、将特定于药物的信息限制在方案附录中以及模块化同意书，实现了对多种药物的快速招募。与食品和药物管理局合作，为在 COVID-19 住院患者中使用人类数据有限的潜在治疗药物制定了全面的安全性数据收集和数据与安全监测委员会计划。
截至 2021 年 8 月 8 日，已有五种药物进入 COVID-19 住院患者治疗方案主方案，共有 1909 名参与者被随机分配到这些药物之一或匹配的安慰剂中。研究团队在成功实施 COVID-19 住院患者治疗方案方面面临了许多挑战，需要在全球站点网络中克服这些挑战。这些挑战包括确保药物供应和可靠的招募，以适应全球站点网络中不断变化的感染率，需要在不增加临床工作人员负担的情况下平衡数据和样本的收集，并在全球站点网络中获得监管批准。
通过稳健的多网络合作，COVID-19 住院患者治疗方案已成功在全球站点网络中使用，快速生成多种新型抗病毒药物的疗效数据。该方案中使用的方案设计和实施特点，以及解决挑战的方法，将具有更广泛的适用性。需要建立机制，以促进各国监管机构之间的更好沟通和协调，以充分发挥这种方法在应对全球疫情爆发方面的潜力。
