Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.
Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.
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DOI：
10.1016/s2213-2600(21)00460-4
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发表时间：
2022-03
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影响因子：
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通讯作者：
CATALYST investigators
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作者：
Fisher BA;Veenith T;Slade D;Gaskell C;Rowland M;Whitehouse T;Scriven J;Parekh D;Balasubramaniam MS;Cooke G;Morley N;Gabriel Z;Wise MP;Porter J;McShane H;Ho LP;Newsome PN;Rowe A;Sharpe R;Thickett DR;Bion J;Gates S;Richards D;Kearns P;CATALYST investigators
炎症失调与COVID-19的不良结局相关。我们的目的是评估纳米单抗（一种粒细胞-巨噬细胞集落刺激因子抑制剂）和英夫利西单抗（一种肿瘤坏死因子抑制剂）在住院的COVID-19患者中的疗效，以优先考虑III期试验的药物。在这项随机、多中心、多组、多阶段、平行组、开放标签、适应性、2期、概念验证试验（CATALYST）中，我们招募了英国9家医院的COVID-19肺炎和C反应蛋白（CRP）浓度≥ 40 mg/L的住院患者（年龄≥16岁）。参与者以相等的概率被随机分配到常规护理或常规护理加单次静脉注射剂量的那木单抗（150 mg）或英夫利西单抗（5 mg/kg）。按照医院内的护理地点（病房vs重症监护室[ICU]）对随机化进行分层。患者和研究者对治疗分配不设盲。主要终点是炎症的改善，通过CRP浓度随时间的变化进行测量，使用贝叶斯多水平模型进行分析。本试验现已完成，并在ISRCTN注册，编号40580903。在2020年6月15日至2021年2月18日期间，我们筛选了299例患者，其中146例入组并随机分配至常规治疗（n=54），那美单抗（n=57）或英夫利昔单抗（n=35）。对于主要结局，常规治疗组的45例患者与那木单抗组的52例患者进行了比较，常规治疗组的29例患者与英夫利昔单抗组的28例患者进行了比较。干预在随时间降低CRP浓度方面上级单独常规治疗的概率为97%（nam）和15%（infliximab）;治疗-时间相互作用的点估计值为-0statist09（95%CI-0statist19至0.00）（nam）和0.06（-0statist05至0.17）（infliximab）。在那木单抗组中，55名患者中有30名（55%）发生了134起不良事件，而常规治疗组中54名患者中有29名（54%）发生了145起不良事件。英夫利西单抗组29例患者中有20例（69%）发生了102起不良事件，而常规治疗组34例患者中有17例（50%）发生了112起不良事件。死亡发生在6名（11%）患者在那木单抗组与10名（19%）在常规护理组，和4名（14%）在英夫利西单抗组与5名（15%）在常规护理组。纳米尤单抗（而非英夫利西单抗）显示出减少COVID-19肺炎住院患者炎症（通过CRP浓度测量）的概念验证证据。纳米单抗应优先用于COVID-19的进一步研究。医学研究理事会。
Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment–time interactions were –0·09 (95% CI –0·19 to 0·00) for namilumab and 0·06 (–0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation—as measured by CRP concentration—in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. Medical Research Council.