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

AGILE：用于快速评估 COVID-19 治疗候选者的无缝 I/IIa 期平台

• 批准号: MR/V028391/1
• 负责人: Saye Khoo
• 金额: $ 809.65万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV028391%2F1
• 关键词: AGILE; Seamless; Phase; IIa; Platform

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).

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的迫切需求。我们现在面临的挑战是加速这一进程，快速确定在大量不同的新化合物和重新利用的药物（用于治疗其他疾病的现有药物）中，哪些可能是拯救生命和变革性的。大规模试验目前正在评估用于治疗COVID-19的“第一波”重新用途药物。如果这些化合物未能证明获益（如羟氯喹、洛匹那韦、托珠单抗、sar等候选药物已经发生的情况），则必须检查一系列替代的“第二波”化合物（临床证据较少）。由于大多数最初看起来很有吸引力的实验性治疗方法最终会被证明是无效的，因此我们找到有效治疗方法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“饲养者”计划，以推进合理的候选人进行临床评价，并消除候选人很少或没有前景的临床成功。AGILE是一个快速临床评估潜在COVID治疗的平台。通过在创新的试验设计中利用现代统计方法，我们能够从首次用于人体到找到用于COVID患者的最佳剂量进行无缝过渡（对于新化合物）。该试验是i）务实的-评估结果在几十个（而不是数百名）患者i）适应性-最初招募一小群参与者，然后（取决于安全性）随后是具有安全性知识的其他类似组，ii）统计学上有效-使用来自“控制”COVID的知识-统计模型中的19例患者允许同时或按顺序评估多组和干预。迅速消除前景不佳的药物。iv）迅速和反应迅速--英国监管机构批准了针对癌症患者的类似“快速通道”方案。AGILE将与已建立的联盟密切合作，为这些联盟提出合理的候选人，以进行大规模试验。每种新化合物都包含在AGILE的一个单独分支中。AGILE的创新功能是在COVID-19参与者中进行测试（首次在人类中进行），能够根据药物在现实生活中的预期部署量身定制研究终点和参与者。这意味着抗病毒药物（AGILE的主要重点）的测试在医院外的社区环境中进行，并且在患有轻中度疾病的人群中进行，因为这是这些药物最有可能被用于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。为了实现这一目标，我们建议建立一个全英国的AGILE网站网络，成为一个测试新型冠状病毒药物的单一国家平台。AGILE已获得监管部门的全面批准，但目前仅在英国的一个地点（利物浦）运营。

项目成果

The development and validation of a novel LC-MS/MS method for the simultaneous quantification of Molnupiravir and its metabolite ß-d-N4-hydroxycytidine in human plasma and saliva.

• DOI: 10.1016/j.jpba.2021.114356
• 发表时间: 2021-11-30
• 期刊: Journal of pharmaceutical and biomedical analysis
• 影响因子: 3.4
• 作者: Amara A;Penchala SD;Else L;Hale C;FitzGerald R;Walker L;Lyons R;Fletcher T;Khoo S
• 通讯作者: Khoo S

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

Molnupiravir 与安慰剂在英国未接种疫苗和接种疫苗的早期 SARS-CoV-2 感染患者中的比较 (AGILE CST-2)：一项随机、安慰剂对照、双盲 2 期试验。

• DOI: 10.17863/cam.91608
• 发表时间: 2023
• 作者: Khoo S

AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter.

• DOI: 10.1186/s13063-021-05458-4
• 发表时间: 2021-07-26
• 期刊: Trials
• 影响因子: 2.5
• 作者: Griffiths GO;FitzGerald R;Jaki T;Corkhill A;Reynolds H;Ewings S;Condie S;Tilt E;Johnson L;Radford M;Simpson C;Saunders G;Yeats S;Mozgunov P;Tansley-Hancock O;Martin K;Downs N;Eberhart I;Martin JWB;Goncalves C;Song A;Fletcher T;Byrne K;Lalloo DG;Owen A;Jacobs M;Walker L;Lyon R;Woods C;Gibney J;Chiong J;Chandiwana N;Jacob S;Lamorde M;Orrell C;Pirmohamed M;Khoo S;AGILE investigators
• 通讯作者: AGILE investigators

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

• DOI: 10.1038/s41467-022-34839-9
• 发表时间: 2022-11-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Donovan-Banfield, I'ah;Penrice-Randal, Rebekah;Goldswain, Hannah;Rzeszutek, Aleksandra M.;Pilgrim, Jack;Bullock, Katie;Saunders, Geoffrey;Northey, Josh;Dong, Xiaofeng;Ryan, Yan;Reynolds, Helen;Tetlow, Michelle;Walker, Lauren E.;FitzGerald, Richard;Hale, Colin;Lyon, Rebecca;Woods, Christie;Ahmad, Shazaad;Hadjiyiannakis, Dennis;Periselneris, Jimstan;Knox, Emma;Middleton, Calley;Lavelle-Langham, Lara;Shaw, Victoria;Greenhalf, William;Edwards, Thomas;Lalloo, David G.;Edwards, Christopher J.;Darby, Alistair C.;Carroll, Miles W.;Griffiths, Gareth;Khoo, Saye H.;Hiscox, Julian A.;Fletcher, Thomas
• 通讯作者: Fletcher, Thomas

Development and validation of an LC-MS/MS method for quantification of favipiravir in human plasma

• DOI: 10.1016/j.jpba.2023.115436
• 发表时间: 2023-05-04
• 期刊: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
• 影响因子: 3.4
• 作者: Challenger, Elizabeth;Penchala, Sujan Dilly;Else, Laura
• 通讯作者: Else, Laura