Leronlimab治疗轻度至中度COVID-19的随机安慰剂对照试验。

IF 3.2 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Harish Seethamraju MD , Otto O. Yang MD , Richard Loftus MD , Onyema Ogbuagu MD , Daniel Sammartino MD , Ali Mansour MD , Jonah B. Sacha PhD , Sohita Ojha PhD , Scott G. Hansen PhD , Arvin Cyrus Arman PhD , Jacob P. Lalezari MD
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引用次数: 0

摘要

目的:在 SARS-CoV-2 大流行的早期,有一种假设认为宿主基因在 COVID-19 的病理生理学中起了一定作用,包括 CCR5-Δ32 突变可能对 SARS-CoV-2 感染具有保护作用。Leronlimab是一种正在研究中的CCR5特异性人源化IgG4单克隆抗体,目前正在开发用于治疗HIV-1感染。我们旨在探讨来龙利单抗对轻度至中度 COVID-19 感染者疾病症状严重程度的影响:TEMPEST试验是一项随机、双盲、安慰剂对照研究,研究对象为轻度至中度COVID-19患者。参与者按2:1的比例随机分配在第0天和第7天接受皮下注射来龙利单抗(700毫克)或安慰剂。主要疗效终点根据治疗结束时(第14天)发热、肌痛、呼吸困难和咳嗽等症状总分的变化进行评估:共有84名参与者接受了随机治疗,其中56人接受了来龙利单抗治疗,28人接受了安慰剂治疗。在总症状评分变化(P = 0.8184)或其他预先指定的次要终点方面,未观察到不同治疗之间存在差异。然而,在一项事后分析中,50.0%接受来龙利单抗治疗的参与者在第14天时的全国预警评分2(NEWS2)比基线有所改善,而安慰剂组中只有20-8%的参与者有所改善(事后分析;P = 0.0223)。在该试验的参与者中,轻度至中度 COVID-19 不良事件的发生率在数量上低于安慰剂参与者(50.0%),但在统计学上并无显著差异:在设计 TEMPEST 试验时,虽然人们知道 CCR5 与 COVID-19 疾病的严重程度有关,但对 SARS-CoV-2 感染的确切病理生理学却知之甚少。如今,人们普遍认为,SARS-CoV-2 感染在无症状到轻度病例中主要表现为病毒复制,免疫反应增强,中重度病例中病毒复制减少,重症病例中炎症反应达到高峰,促炎症细胞因子分泌过多。因此,在轻度至中度 COVID-19 患者的主要终点或预先指定的次要终点中未观察到不同治疗方法之间的差异,也许并不令人惊讶。然而,探索性事后分析结果显示,与安慰剂相比,来龙利单抗组参与者的NEWS2评估结果改善更大,这表明来龙利单抗可能会降低轻度至中度COVID-19患者发展为更严重疾病的可能性,这需要在其他适当设计的临床试验中得到证实。Clinicaltrials: gov number, NCT04343651 https://classic.Clinicaltrials: gov/ct2/show/NCT04343651。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19

Purpose

Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.

Methods

The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).

Findings

Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).

Implications

At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.
ClinicalTrials.gov number, NCT04343651 https://classic.clinicaltrials.gov/ct2/show/NCT04343651
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来源期刊
Clinical therapeutics
Clinical therapeutics 医学-药学
CiteScore
6.00
自引率
3.10%
发文量
154
审稿时长
9 weeks
期刊介绍: Clinical Therapeutics provides peer-reviewed, rapid publication of recent developments in drug and other therapies as well as in diagnostics, pharmacoeconomics, health policy, treatment outcomes, and innovations in drug and biologics research. In addition Clinical Therapeutics features updates on specific topics collated by expert Topic Editors. Clinical Therapeutics is read by a large international audience of scientists and clinicians in a variety of research, academic, and clinical practice settings. Articles are indexed by all major biomedical abstracting databases.
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