Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
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DOI：
10.1016/s2213-2600(21)00081-3
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发表时间：
2021-05
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通讯作者：
Ramanan AV
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作者：
Soin AS;Kumar K;Choudhary NS;Sharma P;Mehta Y;Kataria S;Govil D;Deswal V;Chaudhry D;Singh PK;Gupta A;Agarwal V;Kumar S;Sangle SA;Chawla R;Narreddy S;Pandit R;Mishra V;Goel M;Ramanan AV
抗IL-6受体抗体托珠单抗在因COVID-19入院的患者中进行的全球随机对照试验显示了相互矛盾的结果，但出院时间和重症监护负担可能会减少。托珠单抗在一项富含种族和少数民族的试验人群中减少了机械通气进展和死亡。我们的目的是在第一项完全在中低收入国家进行的托珠单抗多中心随机对照试验中研究托珠单抗治疗是否可以预防COVID-19进展。COVINTOC是一项开放标签，多中心，随机，对照，3期试验，在印度的12家公立和私立医院进行。经SARS-CoV-2 PCR阳性结果证实的中重度COVID-19（印度卫生部分级）住院的成人（年龄≥18岁）被随机分配（1：1区组随机化）接受托珠单抗6 mg/kg+标准治疗（托珠单抗组）或仅接受标准治疗（标准治疗组）。主要终点是在至少有一次主要终点基线后评估的所有参与者的改良意向治疗人群中，COVID-19进展（从中度至重度或从重度至死亡）至第14天。在所有随机分配的患者中评估安全性。该试验已完成并在印度临床试验注册中心注册（CTRI/2020/05/025369）。在2020年5月30日至2020年8月31日期间招募了180名患者，并随机分配到托珠单抗组（n=90）或标准治疗组（n=90）。1例随机分配至标准治疗组的患者在基线时意外接受了托珠单抗治疗，并被纳入托珠单抗组进行所有分析。1例随机分配至标准治疗组的患者在基线访视后撤回知情同意，未接受任何研究药物，未纳入改良的意向治疗人群，但仍纳入安全性分析。托珠单抗组91人中的75人（82%）和标准治疗组89人中的68人（76%）完成了28天的随访。托珠单抗组91例患者中有8例（9%）和标准治疗组88例患者中有11例（13%）的COVID-19进展至第14天（差异-3.71 [95%CI-18.23至11.19]; p= 0.42）。托珠单抗组91例患者中有33例（36%）和标准治疗组89例患者中有22例（25%）发生不良事件; 18例（20%）和15例（17%）发生严重不良事件。最常见的不良事件是急性呼吸窘迫综合征，每组有7例（8%）患者报告。托珠单抗组2例（2%）患者和标准治疗组5例（6%）患者报告了3级不良事件。无4级不良事件。托珠单抗组18例（20%）患者和标准治疗组15例（17%）患者报告了严重不良事件;研究期间分别有13例（14%）和15例（17%）患者死亡。不支持在中重度COVID-19住院患者中常规使用托珠单抗。然而，这项研究的事后证据表明，托珠单抗可能对重度COVID-19患者仍然有效，因此应在未来的研究中进一步研究。Medanta Institute of Education and Research，Roche India，Cipla India，and Action COVID-19 India.
Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference −3·71 [95% CI −18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.