Anakinra, COVID-19, Cytokine Storm

Summary

The clinical syndrome associated with infection of the Coronavirus Disease 2019 (COVID-19) is notable for its variable clinical expression. Infection and transmission of the virus by asymptomatic individuals have been noted and represent one end of the clinical spectrum, while multi-organ failure, particularly pulmonary failure, and death represent the most severe end of the clinical spectrum. In a recent study published from the investigator's institution about the first 393 patients with COVID-19, 77.1% had a fever, a mechanism driven by IL-1. This suggests that there may be an excess release of IL-1 present. Cytokine storm syndrome (CSS) has been observed in patients with COVID-19 and has been proposed to contribute to the acute pulmonary failure that occurs. In distinct clinical settings, macrophage activation syndrome, elevated levels of pro-inflammatory cytokines, including IL-1, IL-6, and others, as well as elevations in laboratory indicators, including ferritin, CRP, d-dimer, and lymphopenia, have been observed. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. Anakinra, a recombinant IL-1 receptor antagonist, has shown promise in treating CSS. It inhibits both IL-1-alpha and IL-1-beta. It is an FDA approved medication used in rheumatoid arthritis (RA) and Cryopyrin-Associated Periodic Syndromes (CAPS). Anakinra's ability to inhibit both IL-1 subtypes and short half-life makes it favorable to some experts. In the investigator's case-series, using anakinra in patients with COVID-19 showed promising in preventing the need for mechanical ventilation, and mortality subsequently. This study will determine the efficacy of anakinra, an interleukin (IL) -1 receptor blocker, in reducing the need for mechanical ventilation and/or 28-day mortality among patients with COVID-19 who have features of CSS and severe respiratory failure. The investigators will test the hypothesis that the proportion of subjects with COVID-19, features of CSS, and severe respiratory failure (World Health Organization (WHO) category 4 or 5) alive and without having required mechanical ventilation at day 28 from randomization will be 18% higher among those that receive anakinra compared to those that receive a placebo. A secondary hypothesis is that the number of subjects alive at 60-days will be higher amongst those who receive anakinra compared to those who receive a placebo.

Timeline

Start

2021-12

Primary completion

2022-06

Completion

2022-09

Publications

• Background Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, Li P, Zhou Y, Lin YF, Duan Q, Luo G, Fan S, Lu Y, Feng A, Zhan Y, Liang B, Cai W, Zhang L, Du X, Li L, Shu Y, Zou H. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect. 2020 Jun;80(6):656-665. doi: 10.1016/j.jinf.2020.03.041. Epub 2020 Apr 10.
• Background Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
• Background Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.
• Background Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
• Background Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR Jr, Nahid M, Ringel JB, Hoffman KL, Alshak MN, Li HA, Wehmeyer GT, Rajan M, Reshetnyak E, Hupert N, Horn EM, Martinez FJ, Gulick RM, Safford MM. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020 Jun 11;382(24):2372-2374. doi: 10.1056/NEJMc2010419. Epub 2020 Apr 17. No abstract available.
• Background Dinarello CA. The history of fever, leukocytic pyrogen and interleukin-1. Temperature (Austin). 2015 Apr 14;2(1):8-16. doi: 10.1080/23328940.2015.1017086. eCollection 2015 Jan-Mar.
• Background WHO. Coronavirus disease (COVID-19) Therapeutic Trial Synopsis. 2020; https://www.who.int/blueprint/priority-diseases/key-action/COVID19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf. Accessed May 8, 2020, 2020.
• Background Navarro-Millan I, Sattui SE, Lakhanpal A, Zisa D, Siegel CH, Crow MK. Use of Anakinra to Prevent Mechanical Ventilation in Severe COVID-19: A Case Series. Arthritis Rheumatol. 2020 Dec;72(12):1990-1997. doi: 10.1002/art.41422. Epub 2020 Nov 4.

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