Piemonti Lorenzo, Landoni Giovanni, Voza Antonio, Puoti Massimo, Gentile Ivan, Coppola Nicola, Nava Stefano, Mattei Alessia, Marinangeli Franco, Marchetti Giulia, Bonfanti Paolo, Mastroianni Claudio Maria, Bassetti Matteo, Crisafulli Ernesto, Grossi Paolo Antonio, Zangrillo Alberto, Desai Antonio, Merli Marco, Foggia Maria, Carpano Marco, Schiavoni Lorenzo, D'Arminio Monforte Antonella, Bisi Luca, Russo Gianluca, Busti Fabiana, Rovelli Cristina, Perrotta Elisabetta, Goisis Giovanni, Gavioli Elizabeth M, Toya Sophie, De Pizzol Maria, Mantelli Flavio, Allegretti Marcello, Minnella Enrico Maria
Diabetes Research Institute, IRCCS Ospedale San Raffaele, Via Olgettina 60. 20132, Milan, Italy.
Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Infect Dis Ther. 2023 Oct;12(10):2437-2456. doi: 10.1007/s40121-023-00871-5. Epub 2023 Oct 5.
Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia.
In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28.
Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment.
This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated.
ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51.
多形核细胞流入间质和支气管肺泡腔是重症2019冠状病毒病（COVID-19）的主要特征，主要由白细胞介素-8（IL-8）介导。我们试图确定新型IL-8途径抑制剂瑞帕昔能否降低重症COVID-19肺炎住院患者的疾病进展。
在这项3期、随机、双盲、安慰剂对照、多中心研究中，将重症COVID-19肺炎住院成年患者按2:1随机分组，接受口服瑞帕昔1200mg，每日3次，或安慰剂，最长21天或直至出院。主要终点是第28天时存活且无呼吸衰竭的患者比例，关键次要终点是第60天时无呼吸衰竭的患者比例、第28天时重症监护病房（ICU）收治率以及第28天时的恢复时间。
279例随机分组患者中，182例接受了至少一剂瑞帕昔，88例接受了安慰剂。两组第28天时存活且无呼吸衰竭的患者比例相似{83.5%对80.7%；优势比1.63[95%置信区间（CI）0.75，3.51]；p = 0.216}。关键次要终点无统计学显著差异，但瑞帕昔组第60天时存活且无呼吸衰竭的患者比例在数值上更高（88.7%对84.6%；p = 0.195），第28天时需要入住ICU的患者更少（15.8%对21.7%；p = 0.168），与安慰剂相比，第28天时恢复的患者比例更高（81.6%对74.9%；p = 0.167）。与安慰剂相比，瑞帕昔治疗的患者不良事件更少（45.6%对54.5%），大多为轻度或中度，且与研究治疗无关。
该试验未达到主要疗效终点，但瑞帕昔作为COVID-19重症肺炎的附加治疗显示出限制疾病进展的趋势，且耐受性良好。
ClinicalTrials.gov：NCT04878055，EudraCT：2020-005919-51。
