Hepprich Matthias, Mudry Jonathan M, Gregoriano Claudia, Jornayvaz Francois R, Carballo Sebastian, Wojtusciszyn Anne, Bart Pierre-Alexandre, Chiche Jean-Daniel, Fischli Stefan, Baumgartner Thomas, Cavelti-Weder Claudia, Braun Dominique L, Günthard Huldrych F, Beuschlein Felix, Conen Anna, West Emily, Isenring Egon, Zechmann Stefan, Bucklar Gabriela, Aubry Yoann, Dey Ludovic, Müller Beat, Hunziker Patrick, Schütz Philipp, Cattaneo Marco, Donath Marc Y
University Hospital Basel, Division of Endocrinology, Diabetes and Metabolism, Basel, Switzerland.
Medical University Department of Medicine, Kantonsspital Aarau, Aarau, Switzerland.
EClinicalMedicine. 2022 Sep 17;53:101649. doi: 10.1016/j.eclinm.2022.101649. eCollection 2022 Nov.
Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1β (IL-1β) blockade using canakinumab improves clinical outcome.
CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493.
Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group.
In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation.
Swiss National Science Foundation # and University of Basel. Novartis supplied study medication.
2型糖尿病和肥胖患者的先天性免疫系统存在慢性激活，这可能是该人群对严重急性呼吸综合征冠状病毒2（SARS-CoV2）发生高炎症反应及出现重症2019冠状病毒病（COVID-19）风险较高的原因。我们测试了使用卡那单抗阻断白细胞介素-1β（IL-1β）是否能改善临床结局。
CanCovDia是一项多中心、随机、双盲、安慰剂对照试验，旨在评估在瑞士七家三级医院因SARS-CoV2感染住院的2型糖尿病且体重指数（BMI）>25kg/m²的患者中，卡那单抗加标准治疗与安慰剂加标准治疗的疗效。患者按1:1随机分配至单次静脉注射卡那单抗（根据体重调整剂量为450 - 750mg）或安慰剂组。基于生存时长、通气时间、重症监护病房（ICU）住院时间和第29天的住院时间，采用非配对胜率法比较卡那单抗和安慰剂。本研究已在ClinicalTrials.gov注册，注册号为NCT04510493。
2020年10月17日至2021年5月12日期间，116例患者被随机分组，每组58例。每组各有1名参与者退出主要分析。随机分组时，85例患者（74.6%）接受了地塞米松治疗。卡那单抗与安慰剂的胜率为1.08（95%置信区间0.69 - 1.69；p = 0.72）。四周内，卡那单抗组与安慰剂组分别有4例（7.0%）和7例（12.3%）参与者死亡，11例（20.0%）和16例（28.1%）患者入住ICU，12例（23.5%）和11例（21.6%）患者住院超过3周。卡那单抗组与安慰剂组四周时的中位通气时间分别为10天[四分位间距（IQR）6.0，16.5]和16天[IQR 14.0，23.0]。尽管接受卡那单抗治疗的患者使用的抗糖尿病药物数量较少，但四周后糖化血红蛋白（HbA1c）无统计学显著差异。最后，卡那单抗降低了高敏C反应蛋白（hs-CRP）和IL-6水平。每组有13例患者（11.4%）报告了严重不良事件。
在因COVID-19住院的2型糖尿病患者中，除标准治疗外加用卡那单抗治疗并未使主要复合结局有统计学显著改善。接受卡那单抗治疗的患者达到相似血糖控制所需的抗糖尿病药物明显更少。卡那单抗与全身炎症的持续减轻相关。
瑞士国家科学基金会#以及巴塞尔大学。诺华公司提供研究药物。
