Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial.
Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial.
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DOI：
10.1016/s0140-6736(22)00101-5
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发表时间：
2022-02-05
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通讯作者：
ITAC (INSIGHT 013) Study Group
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作者：
ITAC (INSIGHT 013) Study Group
使用源自康复供者的超免疫静脉免疫球蛋白 (hIVIG) 针对 SARS-CoV-2 的被动免疫疗法是针对 SARS-CoV-2 等爆发性感染的一种潜在的快速可用的特异性疗法。 hIVIG 治疗 COVID-19 的随机临床试验的结果有限。在这项国际随机、双盲、安慰剂对照试验中，有症状长达 12 天且没有急性终末器官衰竭的 COVID-19 住院患者被随机分配 (1:1) 接受 hIVIG 或等量生理盐水作为安慰剂，此外，如果没有禁忌症，除瑞德西韦外，还接受其他标准临床护理。随机分组按现场药房分层；时间表是使用质量加权瓮设计来准备的。输液由试验药剂师配制和掩蔽；所有其他调查人员、研究人员和试验参与者都对分组分配不知情。随访28天。主要结局在第 7 天通过七类顺序终点进行测量，该终点考虑了肺部状况和肺外并发症，范围从无限制症状到死亡。死亡和不良事件（包括器官衰竭和严重感染）被用来定义第 7 天和第 28 天的复合安全性结果。根据症状持续时间、抗尖峰中和抗体的存在和其他基线因素，对疗效和安全性结果进行了预先指定的亚组分析。对修改后的意向治疗（mITT）人群进行了分析，其中包括所有随机分配的符合资格标准并接受全部或部分指定研究产品输注的参与者。本研究已在 ClinicalTrials.gov 注册，NCT04546581。从2020年10月8日到2021年2月10日，在11个国家的63个研究中心招募了593名参与者（n=301 hIVIG，n=292安慰剂）； mITT 分析中纳入了 579 名患者。与安慰剂相比，hIVIG 组在第 7 天获得更有利结果的几率并没有显着增加；调整后的 OR 为 1·06 (95% CI 0·77–1·45；p=0·72)。输注耐受性良好，但输注反应在 hIVIG 组中更为常见（安慰剂组为 18·6% vs 9·5%；p=0·002）。 hIVIG 组 (24%) 和安慰剂组 (25%；OR 0·98，95% CI 0·66–1·46；p=0·91) 在第 7 天的复合安全性结果百分比相似。对于所考虑的亚组，第 7 天顺序结果的 OR 没有变化，但有证据表明第 7 天复合安全性结果的治疗效果存在异质性：对于抗体阳性患者，与安慰剂相比，hIVIG 的风险更大（OR 2·21，95% CI 1·14–4·29）；对于抗体阴性的患者，OR 为 0·51 (0·29–0·90；pinteraction=0·001)。当采用包括瑞德西韦在内的标准护理治疗时，SARS-CoV-2 hIVIG 在没有终末器官衰竭的 COVID-19 住院患者中并未显示出疗效。 hIVIG 的安全性可能因进入时内源性中和抗体的存在而异。美国国立卫生研究院。
Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. US National Institutes of Health.