Akinosoglou Karolina, Kotsaki Antigone, Gounaridi Ioanna-Maria, Christaki Eirini, Metallidis Simeon, Adamis Georgios, Fragkou Archontoula, Fantoni Massimo, Rapti Aggeliki, Kalomenidis Ioannis, Chrysos Georgios, Boni Gloria, Kainis Ilias, Alexiou Zoi, Castelli Francesco, Serino Francesco Saverio, Bakakos Petros, Nicastri Emanuele, Tzavara Vassiliki, Safarika Asimina, Ioannou Sofia, Dagna Lorenzo, Dimakou Katerina, Tzatzagou Glykeria, Chini Maria, Bassetti Matteo, Kotsis Vasileios, Angheben Andrea, Tsoukalas George, Selmi Carlo, Spiropoulou Olga-Maria, Samarkos Michael, Doumas Michael, Damoraki Georgia, Masgala Aikaterini, Papanikolaou Ilias, Argyraki Aikaterini, Negri Marcantonio, Leventogiannis Konstantinos, Sympardi Styliani, Gatselis Nikolaos K, Petrakis Vasileios, Netea Mihai G, Panagopoulos Periklis, Sakka Vissaria, Milionis Haralampos, Dalekos George N, Giamarellos-Bourboulis Evangelos J
Department of Internal Medicine, University of Patras, Rion, Greece.
Fourth Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
EClinicalMedicine. 2023 Feb;56:101785. doi: 10.1016/j.eclinm.2022.101785. Epub 2022 Dec 26.
The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes.
This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949).
Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment.
Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90.
Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.
SAVE-MORE试验表明，在新冠病毒肺炎患者中，血浆可溶性尿激酶型纤溶酶原激活剂（suPAR）水平≥6 ng/mL的患者，与安慰剂相比，使用阿那白滞素治疗后，根据世界卫生组织临床进展量表（CPS）在第28天评估，预后较差的几率为0.36。在此，我们报告亚组分析结果和长期预后情况。
这项前瞻性、双盲、随机临床试验，招募了来自希腊和意大利37家学术及社区医院的确诊感染SARS-CoV-2、需要住院治疗、患有下呼吸道感染且血浆suPAR≥6 ng/mL的患者。患者按1:2随机分为皮下注射安慰剂或阿那白滞素（100 mg）组，每日1次，共10天。按照意向性分析（ITT）人群，通过多变量有序回归分析，对预先定义的Charlson合并症指数（CCI）、性别、年龄、suPAR水平以及症状出现时间的亚组进行主要终点分析（第28天治疗组间WHO-CPS评分频率分布的总体比较）。该试验已在欧盟临床试验注册库（2020-005828-11）和美国国立医学图书馆临床试验数据库（NCT04680949）注册。
患者于2020年12月23日至2021年3月31日入组；ITT人群中，安慰剂组189例患者，阿那白滞素组405例患者。多变量分析显示，在第28天，对于所有研究的亚组，与安慰剂相比，阿那白滞素治疗后预后较差的几率显著降低（CCI≥2，比值比[OR]：0.34，95%置信区间[CI] 0.22 - 0.50；CCI<2，OR：0.38，95% CI 0.21 - 0.68；suPAR>9 ng/mL，OR：0.35，95% CI 0.19 - 0.66；suPAR 6 - 9 ng/mL，OR：0.35，95% CI 0.24 - 0.52；年龄≥65岁患者，OR：0.41，95% CI 0.25 - 0.66；年龄<65岁患者，OR：0.29，95% CI 0.19 - 0.45）。无论从症状开始到研究药物开始使用的时间如何，获益都是一致的。在第60天和第90天，与安慰剂相比，阿那白滞素治疗后预后较差的几率分别为0.40（95% CI 0.28 - 0.57）和0.46（95% CI 0.32 - 0.67）。阿那白滞素治疗的普通病房住院费用、重症监护病房住院费用和药物费用较低。
阿那白滞素是新冠病毒治疗中的一种重要治疗手段，可用于所有亚组患者；获益可持续至第90天。
希腊脓毒症研究协会；瑞典孤儿生物制药公司。
