Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19).
To assess the effectiveness and safety of SARS-CoV-2-neutralising mAbs for treating patients with COVID-19, compared to an active comparator, placebo, or no intervention. To maintain the currency of the evidence, we will use a living systematic review approach. A secondary objective is to track newly developed SARS-CoV-2-targeting mAbs from first tests in humans onwards. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane COVID-19 Study Register, and three other databases on 17 June 2021. We also checked references, searched citations, and contacted study authors to identify additional studies. Between submission and publication, we conducted a shortened randomised controlled trial (RCT)-only search on 30 July 2021.
We included studies that evaluated SARS-CoV-2-neutralising mAbs, alone or combined, compared to an active comparator, placebo, or no intervention, to treat people with COVID-19. We excluded studies on prophylactic use of SARS-CoV-2-neutralising mAbs.
Two authors independently assessed search results, extracted data, and assessed risk of bias using the Cochrane risk of bias tool (RoB2). Prioritised outcomes were all-cause mortality by days 30 and 60, clinical progression, quality of life, admission to hospital, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE.
We identified six RCTs that provided results from 17,495 participants with planned completion dates between July 2021 and December 2031. Target sample sizes varied from 1020 to 10,000 participants. Average age was 42 to 53 years across four studies of non-hospitalised participants, and 61 years in two studies of hospitalised participants. Non-hospitalised individuals with COVID-19 Four studies evaluated single agents bamlanivimab (N = 465), sotrovimab (N = 868), regdanvimab (N = 307), and combinations of bamlanivimab/etesevimab (N = 1035), and casirivimab/imdevimab (N = 799). We did not identify data for mortality at 60 days or quality of life. Our certainty of the evidence is low for all outcomes due to too few events (very serious imprecision). Bamlanivimab compared to placebo No deaths occurred in the study by day 29. There were nine people admitted to hospital by day 29 out of 156 in the placebo group compared with one out of 101 in the group treated with 0.7 g bamlanivimab (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.02 to 1.33), 2 from 107 in the group treated with 2.8 g (RR 0.32, 95% CI 0.07 to 1.47) and 2 from 101 in the group treated with 7.0 g (RR 0.34, 95% CI 0.08 to 1.56). Treatment with 0.7 g, 2.8 g and 7.0 g bamlanivimab may have similar rates of AEs as placebo (RR 0.99, 95% CI 0.66 to 1.50; RR 0.90, 95% CI 0.59 to 1.38; RR 0.81, 95% CI 0.52 to 1.27). The effect on SAEs is uncertain. Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Bamlanivimab/etesevimab compared to placebo There were 10 deaths in the placebo group and none in bamlanivimab/etesevimab group by day 30 (RR 0.05, 95% CI 0.00 to 0.81). Bamlanivimab/etesevimab may decrease hospital admission by day 29 (RR 0.30, 95% CI 0.16 to 0.59), may result in a slight increase in any grade AEs (RR 1.15, 95% CI 0.83 to 1.59) and may increase SAEs (RR 1.40, 95% CI 0.45 to 4.37). Clinical progression/improvement of symptoms or development of severe symptoms were not reported. Casirivimab/imdevimab compared to placebo Casirivimab/imdevimab may reduce hospital admissions or death (2.4 g: RR 0.43, 95% CI 0.08 to 2.19; 8.0 g: RR 0.21, 95% CI 0.02 to 1.79). We are uncertain of the effect on grades 3-4 AEs (2.4 g: RR 0.76, 95% CI 0.17 to 3.37; 8.0 g: RR 0.50, 95% CI 0.09 to 2.73) and SAEs (2.4 g: RR 0.68, 95% CI 0.19 to 2.37; 8.0 g: RR 0.34, 95% CI 0.07 to 1.65). Mortality by day 30 and clinical progression/improvement of symptoms or development of severe symptoms were not reported. Sotrovimab compared to placebo We are uncertain whether sotrovimab has an effect on mortality (RR 0.33, 95% CI 0.01 to 8.18) and invasive mechanical ventilation (IMV) requirement or death (RR 0.14, 95% CI 0.01 to 2.76). Treatment with sotrovimab may reduce the number of participants with oxygen requirement (RR 0.11, 95 % CI 0.02 to 0.45), hospital admission or death by day 30 (RR 0.14, 95% CI 0.04 to 0.48), grades 3-4 AEs (RR 0.26, 95% CI 0.12 to 0.60), SAEs (RR 0.27, 95% CI 0.12 to 0.63) and may have little or no effect on any grade AEs (RR 0.87, 95% CI 0.66 to 1.16). Regdanvimab compared to placebo Treatment with either dose (40 or 80 mg/kg) compared with placebo may decrease hospital admissions or death (RR 0.45, 95% CI 0.14 to 1.42; RR 0.56, 95% CI 0.19 to 1.60, 206 participants), but may increase grades 3-4 AEs (RR 2.62, 95% CI 0.52 to 13.12; RR 2.00, 95% CI 0.37 to 10.70). 80 mg/kg may reduce any grade AEs (RR 0.79, 95% CI 0.52 to 1.22) but 40 mg/kg may have little to no effect (RR 0.96, 95% CI 0.64 to 1.43). There were too few events to allow meaningful judgment for the outcomes mortality by 30 days, IMV requirement, and SAEs. Hospitalised individuals with COVID-19 Two studies evaluating bamlanivimab as a single agent (N = 314) and casirivimab/imdevimab as a combination therapy (N = 9785) were included. Bamlanivimab compared to placebo We are uncertain whether bamlanivimab has an effect on mortality by day 30 (RR 1.39, 95% CI 0.40 to 4.83) and SAEs by day 28 (RR 0.93, 95% CI 0.27 to 3.14). Bamlanivimab may have little to no effect on time to hospital discharge (HR 0.97, 95% CI 0.78 to 1.20) and mortality by day 90 (HR 1.09, 95% CI 0.49 to 2.43). The effect of bamlanivimab on the development of severe symptoms at day 5 (RR 1.17, 95% CI 0.75 to 1.85) is uncertain. Bamlanivimab may increase grades 3-4 AEs at day 28 (RR 1.27, 95% CI 0.81 to 1.98). We assessed the evidence as low certainty for all outcomes due to serious imprecision, and very low certainty for severe symptoms because of additional concerns about indirectness. Casirivimab/imdevimab with usual care compared to usual care alone Treatment with casirivimab/imdevimab compared to usual care probably has little or no effect on mortality by day 30 (RR 0.94, 95% CI 0.87 to 1.02), IMV requirement or death (RR 0.96, 95% CI 0.90 to 1.04), nor alive at hospital discharge by day 30 (RR 1.01, 95% CI 0.98 to 1.04). We assessed the evidence as moderate certainty due to study limitations (lack of blinding). AEs and SAEs were not reported. AUTHORS' CONCLUSIONS: The evidence for each comparison is based on single studies. None of these measured quality of life. Our certainty in the evidence for all non-hospitalised individuals is low, and for hospitalised individuals is very low to moderate. We consider the current evidence insufficient to draw meaningful conclusions regarding treatment with SARS-CoV-2-neutralising mAbs. Further studies and long-term data from the existing studies are needed to confirm or refute these initial findings, and to understand how the emergence of SARS-CoV-2 variants may impact the effectiveness of SARS-CoV-2-neutralising mAbs. Publication of the 36 ongoing studies may resolve uncertainties about the effectiveness and safety of SARS-CoV-2-neutralising mAbs for the treatment of COVID-19 and possible subgroup differences.
单克隆抗体（mAbs）是从受感染宿主的 B 细胞中实验室产生的分子。它们正在被研究作为治疗 2019 年冠状病毒病（COVID-19）的一种潜在疗法。
评估 SARS-CoV-2 中和单克隆抗体治疗 COVID-19 患者的有效性和安全性，与活性对照、安慰剂或不干预相比。为了保持证据的时效性，我们将使用一种活的系统综述方法。次要目标是跟踪从首次人体测试开始的新开发的 SARS-CoV-2 靶向单克隆抗体。
我们检索了 MEDLINE、Embase、Cochrane COVID-19 研究注册库和另外三个数据库，检索日期为 2021 年 6 月 17 日。我们还查阅了参考文献、检索了引文，并联系了研究作者以确定其他研究。在提交和发表之间，我们于 2021 年 7 月 30 日进行了一次仅随机对照试验（RCT）的简短检索。
我们纳入了评估 SARS-CoV-2 中和单克隆抗体单独或联合治疗 COVID-19 患者的研究，与活性对照、安慰剂或不干预相比。我们排除了预防性使用 SARS-CoV-2 中和单克隆抗体的研究。
两名作者独立评估了搜索结果、提取数据，并使用 Cochrane 偏倚风险工具（RoB2）评估了偏倚风险。优先结局是第 30 天和第 60 天的全因死亡率、临床进展、生活质量、住院、不良事件（AE）和严重不良事件（SAE）。我们使用 GRADE 评估证据的确定性。
我们确定了六项 RCT，这些研究提供了计划完成日期在 2021 年 7 月至 2031 年 12 月之间的 17495 名参与者的结果。目标样本量从 1020 到 10000 名参与者不等。四项非住院患者研究的平均年龄为 42 至 53 岁，两项住院患者研究的平均年龄为 61 岁。非住院 COVID-19 患者：四项研究评估了单剂巴伦单抗（N=465）、索托里单抗（N=868）、雷丹维单抗（N=307）以及巴伦单抗/etesevimab（N=1035）和卡西里单抗/伊德维单抗（N=799）的组合。我们没有发现关于 60 天死亡率或生活质量的数据。由于事件太少（非常严重的不精确），我们对所有结局的证据确定性都为低。
第 29 天，研究中没有发生死亡事件。与安慰剂组 156 人相比，0.7g 巴伦单抗组有 9 人（RR 0.17，95%CI 0.02 至 1.33），29 天住院，与 107 人相比，2.8g 巴伦单抗组有 2 人（RR 0.32，95%CI 0.07 至 1.47），与 101 人相比，7.0g 巴伦单抗组有 2 人（RR 0.34，95%CI 0.08 至 1.56）。0.7g、2.8g 和 7.0g 巴伦单抗的治疗与安慰剂相比，AE（RR 0.99，95%CI 0.66 至 1.50；RR 0.90，95%CI 0.59 至 1.38；RR 0.81，95%CI 0.52 至 1.27）和 SAE（RR 0.99，95%CI 0.66 至 1.50；RR 0.90，95%CI 0.59 至 1.38；RR 0.81，95%CI 0.52 至 1.27）的发生率可能相似。对 SAE 的影响不确定。没有报告临床进展/症状改善或严重症状的发生。
巴伦单抗/etesevimab 与安慰剂：在安慰剂组中，第 30 天有 10 人死亡，而在巴伦单抗/etesevimab 组中，第 30 天没有人死亡（RR 0.05，95%CI 0.00 至 0.81）。与安慰剂相比，巴伦单抗/etesevimab 可能会减少第 29 天的住院人数（RR 0.30，95%CI 0.16 至 0.59），可能会导致任何等级的 AE（RR 1.15，95%CI 0.83 至 1.59）略有增加，并且可能会增加 SAE（RR 1.40，95%CI 0.45 至 4.37）。没有报告临床进展/症状改善或严重症状的发生。
卡西里单抗/伊德维单抗与安慰剂：与安慰剂相比，卡西里单抗/伊德维单抗可能会降低住院或死亡的风险（2.4g：RR 0.43，95%CI 0.08 至 2.19；8.0g：RR 0.21，95%CI 0.02 至 1.79）。我们不确定 3 至 4 级 AE（2.4g：RR 0.76，95%CI 0.17 至 3.37；8.0g：RR 0.50，95%CI 0.09 至 2.73）和 SAE（2.4g：RR 0.68，95%CI 0.19 至 2.37；8.0g：RR 0.34，95%CI 0.07 至 1.65）的效果。没有报告第 30 天的死亡率和临床进展/症状改善或严重症状的发生。
