背景:中性粒细胞丝氨酸蛋白酶参与COVID-19的发病机制,据报道,严重和致命感染中丝氨酸蛋白酶活性增加。我们调查了Brensocatib,二肽基肽酶-1(DPP-1;一种负责激活中性粒细胞丝氨酸蛋白酶的酶)的抑制剂,将改善COVID-19住院患者的预后。
方法:在多中心中,双盲,随机化,平行组,安慰剂对照试验,在英国的14家医院,16岁及以上因COVID-19住院且至少有一个严重疾病危险因素的患者在入院后96小时内被随机分配1:1,每天一次的布伦索马替布25毫克或安慰剂口服28天。患者通过中央基于网络的随机化系统(TruST)随机分配。随机分组按地点和年龄(65岁或≥65岁)分层,在每个地层中,块的大小随机为两个,四,或者六个病人.两组参与者继续接受其他治疗,以控制他们的病情。参与者,研究人员,研究人员被掩盖在研究任务中。主要结果是随机分配后第29天的7点WHO序贯临床状态量表。意向治疗人群包括所有被随机分配并符合登记标准的患者。安全性人群包括接受至少一剂研究药物的所有参与者。这项研究在ISRCTN注册中心注册,ISRCTN30564012。
结果:在2020年6月5日至2021年1月25日之间,406例患者被随机分配到brensocatib或安慰剂组;192例(47·3%)归入brensocatib组,214例(52·7%)归入安慰剂组。两名参与者在被随机分配到brensocatib组后被排除在外(在意向治疗人群中,安慰剂组包括214名患者,brensocatib组包括190名患者)。6例患者的主要结局数据不可用(3例在brensocatib组,3例在安慰剂组)。在随机分配后第29天,brensocatib组的患者的临床状况比安慰剂组的患者更差(调整后比值比0·72[95%CI0·57-0·92])。预先确定的主要结局的亚组分析支持主要结果。185例参与者报告了至少一个不良事件;安慰剂组99例(46%),brensocatib组86例(45%)。最常见的不良事件是胃肠道疾病和感染。安慰剂组中的1例死亡被认为可能与研究药物有关。
结论:Brensocatib治疗在第29天没有改善COVID-19住院患者的临床状况。
背景:由邓迪大学赞助,并通过InsMed的研究者发起的研究奖提供支持,布里奇沃特,新泽西州;STOP-COVID19试验。
Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.
In a multicentre, double-blind, randomised, parallel-group, placebo-controlled
trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants,
study staff, and investigators were masked to the
study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This
study was registered with the ISRCTN registry, ISRCTN30564012.
Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to
study drug.
Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.
Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19
trial.