Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial.
Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial.
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DOI：
10.1016/j.eclinm.2023.101889
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发表时间：
2023-04
影响因子：
15.1
通讯作者：
Files, D. Clark
中科院分区：
文献类型：
--
作者：
Files, D. Clark
迫切需要快速筛选用于严重COVID-19或与高发病率和死亡率相关的其他新兴病原体的潜在治疗剂。使用为快速评估研究药物而创建的自适应平台设计，将需要≥6 L/min氧气的重度COVID-19住院患者随机分配至地塞米松和Remdesivir单药（对照）或骨干加一种开放标签研究药物的骨干方案。患者于2020年7月30日至2021年6月11日期间在美国的20个医疗中心入组所述组。该平台包含最多4种潜在可用的研究药物和对照药物，可在单个时间段内进行随机化。两个主要终点是恢复时间（连续两天<6 L/min氧气）和死亡率。每两周评估一次数据，与预先规定的分级标准（即，可能的有效性）、无效性和安全性，适应性样本量为每种药物40-125人，采用贝叶斯分析方法。标准的目的是实现快速筛选的代理商，并确定大的利益信号。同时入组的对照组用于所有分析。https://clinicaltrials.gov/ct2/show/NCT04488081.评价的前7种药物为赛尼克韦罗（CCR 2/5拮抗剂; n = 92）、艾替班特（缓激肽拮抗剂; n = 96）、阿普斯特（PDE 4抑制剂; n = 67）、塞来昔布/法莫替丁（COX 2/组胺阻断剂; n = 30）、IC 14（抗CD 14; n = 67）、α-脱氧核糖核酸酶（吸入性DNA酶; n = 39）和雷扎普他非（Tie 2激动剂; n = 22）。由于可行性问题，Razurotafib被从试验中删除。在改良的意向治疗分析中，没有药物符合预先规定的疗效/分级终点，恢复的风险比[HR] ≤1.5的后验概率在0.99和1.00之间。数据监查委员会因潜在伤害而停用塞来昔布/法莫替丁（恢复的中位后验HR为0.5，95%可信区间[CrI]为0.28-0.90;死亡的中位后验HR为1.67，95% CrI为0.79-3.58）。进入试验的前7种药物均不符合预先规定的大疗效信号标准。塞来昔布/法莫替丁因潜在危害而提前停用。适应性平台试验可能提供一种有用的方法，在大流行期间快速筛选多种药物。Quantum Leap Healthcare Collaborative是试验申办者。这项试验的资金来自：、美国政府根据MCDC和政府之间的其他交易编号W15 QKN-16-9-1002发起的努力。
An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6 L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40–125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n = 92), icatibant (bradykinin antagonist; n = 96), apremilast (PDE4 inhibitor; n = 67), celecoxib/famotidine (COX2/histamine blockade; n = 30), IC14 (anti-CD14; n = 67), dornase alfa (inhaled DNase; n = 39) and razuprotafib (Tie2 agonist; n = 22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28–0.90; median posterior HR for death 1.67, 95% CrI 0.79–3.58). None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic. Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the , , , , , , , /, , FAST Grant from Emergent Venture , The DoD (DTRA), The (BARDA), and The . Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.
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DOI：
10.1016/s2213-2600(22)00215-6
发表时间：
2022-10
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/s2213-2600(21)00105-3
发表时间：
2021-08
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Matthay MA;Thompson BT;Ware LB
通讯作者：
Ware LB
影响因子：
158.5
作者：
Beigel, John H.;Tomashek, Kay M.;Lane, H. Clifford
通讯作者：
Lane, H. Clifford
影响因子：
168.9
作者：
Wang, Yeming;Zhang, Dingyu;Wang, Chen
通讯作者：
Wang, Chen
DOI：
10.1164/rccm.202112-2836oc
发表时间：
2022-09-15
影响因子：
24.7
作者：
Douin, David J.;Siegel, Lianne;Grandits, Greg;Phillips, Andrew;Aggarwal, Neil R.;Baker, Jason;Brown, Samuel M.;Chang, Christina C.;Goodman, Anna L.;Grund, Birgit;Higgs, Elizabeth S.;Hough, Catherine L.;Murray, Daniel D.;Paredes, Roger;Parmar, Mahesh;Pett, Sarah;Polizzotto, Mark N.;Sandkovsky, Uriel;Self, Wesley H.;Young, Barnaby E.;Babiker, Abdel G.;Davey, Victoria J.;Kan, Virginia;Gelijns, Annetine C.;Matthews, Gail;Thompson, B. Taylor;Lane, H. Clifford;Neaton, James D.;Lundgren, Jens D.;Ginde, Adit A.
通讯作者：
Ginde, Adit A.