The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, Ohio.
Ascension St Agnes Cancer Institute, Baltimore, Maryland.
JAMA Netw Open. 2022 Dec 1;5(12):e2242918. doi: 10.1001/jamanetworkopen.2022.42918.
The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated.
To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022.
Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days.
The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed.
A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]).
The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects.
ClinicalTrials.gov Identifier: NCT04404361.
尽管标准治疗有所进展，但 COVID-19 相关的发病率和死亡率仍然很高，抑制白细胞介素 6/JAK2 通路的抗炎药物的作用仍在阐明之中。
评估口服 JAK2/IRAK1 抑制剂 pacritinib 与安慰剂在治疗严重 COVID-19 成人患者中的疗效和安全性。
设计、地点和参与者：这是一项在美国 21 个中心进行的 2 期、双盲、安慰剂对照、随机临床试验，招募了 2020 年 6 月至 2021 年 2 月期间住院的严重 COVID-19 成年患者，每位患者的安全性随访时间约为 1.5 个月。数据分析于 2021 年 9 月至 2022 年 7 月进行。
患者以 1:1 的比例随机分配至标准治疗加 pacritinib（第 1 天口服 400mg，随后第 2-14 天每天口服 200mg）或安慰剂治疗，疗程为 14 天。
第 28 天死亡或需要有创机械通气（IMV）或体外膜氧合（ECMO）。还评估了全因死亡率和安全性。
共有 200 例患者被随机分配至 pacritinib 组（99 例患者；56 名男性[56.6%]；中位[范围]年龄为 60 [19-87]岁）或安慰剂组（101 例患者；64 名男性[63.4%]；中位[范围]年龄为 59 [28-94]岁）。pacritinib 组需要补充氧气的患者比例为 99.0%（98 例），安慰剂组为 98.0%（99 例）。pacritinib 组进展为 IMV、ECMO 或死亡的患者比例为 17.2%（17 例），安慰剂组为 22.8%（23 例）（比值比，0.62；95%CI，0.28-1.35；P=0.23）。在白细胞介素 6 升高的患者中，pacritinib 组的发生率为 17.5%（63 例患者中的 11 例），安慰剂组为 30.4%（96 例患者中的 21 例）。pacritinib 与安慰剂的不良事件发生率相似（78.1%[75 例]与 80.2%[81 例]），感染（14.6%[14 例]与 19.8%[20 例]）、出血（8.3%[8 例]与 10.9%[11 例]）或血栓形成（8.3%[8 例]与 7.9%[8 例]）无差异。pacritinib 组 3 级或以上不良事件发生率低于安慰剂组（29.2%[28 例]与 40.6%[41 例]）。
该研究未达到严重 COVID-19 患者的主要终点。亚组分析可能表明存在过度炎症的特定人群可能受益于 pacritinib，但需要进一步的临床试验来证实这些效果。
ClinicalTrials.gov 标识符：NCT04404361。
