AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment

传统的新药评估时间太长（通常为10年），无法满足治疗和预防COVID-19的迫切需要。我们现在面临的挑战是加快这一进程，在大量多样的新化合物和再用途药物（用于治疗其他疾病的现有药物）中迅速确定哪些可能挽救生命和改变现状。目前正在进行大规模试验，评估用于治疗COVID-19的“第一波”重新用途药物。如果这些化合物未能证明其益处（如羟氯喹、洛匹那韦、托珠单抗、沙伐单抗等候选药物已经出现的情况），则必须研究一系列替代的“第二波”化合物（临床证据较少）。由于大多数最初看起来有吸引力的实验性治疗最终会被证明是无效的，我们找到有效治疗的最佳机会在于尽快筛选和选择最有希望的候选药物。要做到这一点，我们需要一个“喂食”计划，以推进合理的候选人进行临床评估，并淘汰那些很少或没有临床成功前景的候选人。AGILE是一个快速临床评估潜在COVID治疗方法的平台。通过在创新的试验设计中利用现代统计方法，我们能够实现（新化合物）从首次在人体中使用到找到用于COVID患者的最佳剂量的无缝过渡。该试验是务实的——评估数十名（而不是数百名）患者的结果；是适应性的——最初招募一小群参与者，然后（取决于安全性）随后是进一步的类似小组，每个周期都有关于安全性、最佳剂量和疗效的知识。ii)统计效率高——在统计模型中使用来自“对照”COVID-19患者的知识，可以同时或依次评估多个部门和干预措施。几乎没有希望产生中等到显著效果的药物被迅速淘汰。iv)快速反应——英国监管机构批准了针对癌症患者的类似“快速通道”项目。与已建立的联盟紧密合作，AGILE将为这些联盟提供合理的候选方案，以进行大规模试验。每个新化合物都包含在AGILE的一个单独的分支中。AGILE的创新特点是在COVID-19参与者中进行测试（首次在人体中进行），能够根据药物在现实生活中的预期部署定制研究终点和参与者。这意味着抗病毒药物的测试（AGILE的一个主要重点）是在医院以外的社区环境中以及在轻中度疾病患者中进行的，因为这是最有可能使用这些药物来预防严重疾病并减少或预防感染的情况。AGILE旨在快速识别那些可能在对抗covid - 19的战斗中改变游戏规则的化合物。为实现这一目标，我们建议建立一个英国范围内的AGILE站点网络，以成为测试新型COVID药物的单一国家平台。AGILE已经获得了监管部门的全面批准，但目前只在英国的一个站点（利物浦）运行。

Conventional evaluation of new medicines is too lengthy (typically 10 years) to meet the urgent need for treating and preventing COVID-19. Our challenge now is to accelerate this, to quickly identify which amongst the large and diverse list of new compounds and repurposed drugs (existing medicines used for treating other diseases) may be life-saving, and transformational. Large-scale trials are currently evaluating the 'first wave' of repurposed medicines for treating COVID-19. Should these compounds fail to demonstrate benefit (such as has already occurred with candidates such as hydroxychloroquine, lopinavir, tocilizumab, sarilumab), a range of alternative, 'second wave' compounds (with less clinical evidence) have to be examined. Since a majority of experimental treatments which initially seem attractive will eventually prove ineffective, our best chance of finding an effective treatment lies in screening and choosing the most promising candidates as quickly possible. To do this, we need for a 'feeder' programme to advance plausible candidates for clinical evaluation, and to eliminate candidates with little or no prospect of clinical success. AGILE is a platform for rapid clinical evaluation of potential COVID treatments. By harnessing modern statistical methods within an innovative trial design, we are able to make a seamless transition (for new compounds) from first-in-human use to finding the optimal dose for use in COVID patients. The trial is i) Pragmatic - assessing outcomes in dozens (rather than hundreds) of patientsi) Adaptive - a small group of participants are initially enrolled, then (depending on safety) followed by further similar groups, with knowledge of safety, optimal dosing and efficacy accruing with each cycle.ii) Statistically efficient - use of knowledge from 'control' COVID-19 patients within a statistical model allows multiple arms and interventions simultaneously or in sequence to be assessed. Drugs with little prospect of a moderate to significant effect are rapidly eliminated.iv) Rapid and responsive - similar 'fast-track' programmes for cancer patients are approved by the UK regulator. Working closely with established consortia, AGILE will advance plausible candidates for these consortia to test in a large-scale trials. Each new compound is included in a separate arm of AGILE. Innovative features of AGILE are the testing (for the first time in humans) in COVID-19 participants, the ability to tailor the study endpoints and participants to the anticipated deployment of the drug in real-life. This means that testing of antiviral drugs (a major focus of AGILE) takes place in community settings outside hospitals, and in people with mild-moderate disease since this is the scenario where these drugs are most likely to be used, to prevent severe disease, and reduce or prevent infections. AGILE is designed to rapidly identify those compounds which could be game changers in in the battle against COVID19. To achieve this, we propose establishing a UK-wide network of AGILE sites to become a single, national platform for testing new COVID drugs. AGILE has full regulatory approvals, but is currently only operational in one UK site (Liverpool).