Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA.
Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, USA.
Clin Pharmacol Ther. 2021 Mar;109(3):688-696. doi: 10.1002/cpt.2117. Epub 2020 Dec 10.
Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID-19. Results of this trial provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19.
白细胞介素 6（IL-6）介导的过度炎症可能导致 2019 年冠状病毒病（COVID-19）的死亡率升高。IL-6 受体阻断性单克隆抗体托珠单抗已被重新用于 COVID-19，但针对 COVID-19 的前瞻性试验和剂量发现研究尚未完全报告。我们进行了一项非插管住院的 COVID-19 成年患者的低剂量托珠单抗单臂 II 期试验，这些患者存在肺部浸润性放射影像、发热和 C 反应蛋白（CRP）≥40mg/L。我们假设，剂量明显低于新兴的 400mg 或 8mg/kg 标准将解决过度炎症的临床和实验室指标。评估了 40 至 200mg 的剂量范围，允许在 24 至 48 小时时重复一次剂量。主要目的是评估剂量与发热消退和 CRP 反应之间的关系。32 例患者接受了低剂量托珠单抗治疗，大多数患者在给药后 24-48 小时内出现发热消退（75%）和 CRP 下降，这与 IL-6 通路阻断一致（86%）。在 40-200mg 的剂量范围内，没有证据表明剂量与发热消退或 CRP 下降之间存在关系。在 28 天的随访中，有 5（16%）例患者死亡。对于恢复的患者，临床恢复的中位时间为 3 天（四分位距，2-5）。5（16%）例患者报告了临床推测和/或培养的细菌继发感染。低剂量托珠单抗与 COVID-19 住院患者的临床和实验室过度炎症指标的快速改善相关。该试验的结果为 COVID-19 低剂量托珠单抗的随机对照试验提供了依据。
