Early administration of tofacitinib in COVID-19 pneumonitis: An open randomised controlled trial.
Journal
European journal of clinical investigation
ISSN: 1365-2362
Titre abrégé: Eur J Clin Invest
Pays: England
ID NLM: 0245331
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
revised:
03
10
2022
received:
19
08
2022
accepted:
04
10
2022
pubmed:
17
11
2022
medline:
26
1
2023
entrez:
16
11
2022
Statut:
ppublish
Résumé
Controversies on sub-populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID-19. We designed a multicentre open-label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID-19 pneumonitis. Patients admitted to three Italian hospitals affected by COVID-19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission. A total of 116 patients were randomised; 49 in the experimental arm completed the 14-day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO High-dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.
Sections du résumé
BACKGROUND
BACKGROUND
Controversies on sub-populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID-19.
OBJECTIVES
OBJECTIVE
We designed a multicentre open-label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID-19 pneumonitis.
METHODS
METHODS
Patients admitted to three Italian hospitals affected by COVID-19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission.
RESULTS
RESULTS
A total of 116 patients were randomised; 49 in the experimental arm completed the 14-day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO
CONCLUSION
CONCLUSIONS
High-dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.
Substances chimiques
tofacitinib
87LA6FU830
Types de publication
Randomized Controlled Trial
Multicenter Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13898Informations de copyright
© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.
Références
Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-2629.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5
Cron RQ, Caricchio R, Chatham WW. Calming the cytokine storm in COVID-19. Nat Med. 2021;27(10):1674-1675. doi:10.1038/s41591-021-01500-9
Al-Hajeri H, Baroun F, Abutiban F, et al. Therapeutic role of immunomodulators during the COVID-19 pandemic - a narrative review. Postgrad Med. 2022;134(2):160-179. doi:10.1080/00325481.2022.2033563
Burrage DR, Koushesh S, Sofat N. Immunomodulatory drugs in the management of SARS-CoV-2. Front Immunol. 2020;11:1844. doi:10.3389/fimmu.2020.01844
Ghosn L, Chaimani A, Evrenoglou T, et al. Interleukin-6 blocking agents for treating COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;3(3):CD013881. doi:10.1002/14651858.CD013881
Zizzo G, Cohen PL. Imperfect storm: is interleukin-33 the Achilles heel of COVID-19? Lancet Rheumatol. 2020;2(12):e779-e790. doi:10.1016/S2665-9913(20)30340-4
Buszko M, Nita-Lazar A, Park JH, et al. Lessons learned: new insights on the role of cytokines in COVID-19. Nat Immunol. 2021;22(4):404-411. doi:10.1038/s41590-021-00901-9
Liang W, Liang H, Ou L, et al. China medical treatment expert group for COVID-19. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA. Intern Med. 2020;180(8):1081-1089.
Solimando AG, Susca N, Borrelli P, et al. Short-term variations in neutrophil-to-lymphocyte and urea-to-creatinine ratios anticipate intensive care unit admission of COVID-19 patients in the emergency department. Front Med (Lausanne). 2021;20(7):625176.
Zizzo G, Tamburello A, Castelnovo L, et al. Immunotherapy of COVID-19: inside and beyond IL-6 signalling. Front Immunol. 2022;22(13):795315.
Satarker S, Tom AA, Shaji RA, Alosious A, Luvis M, Nampoothiri M. JAK-STAT pathway inhibition and their implications in COVID-19 therapy. Postgrad Med. 2021;133(5):489-507. doi:10.1080/00325481.2020.1855921
Ngamprasertchai T, Kajeekul R, Sivakorn C, et al. Efficacy and safety of immunomodulators in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials. Infect Dis Ther. 2022;11(1):231-248. doi:10.1007/s40121-021-00545-0
Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for treating critically ill hospitalized adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomized, placebo-controlled trial. Lancet Respir Med. 2022;10(4):327-336. doi:10.1016/S2213-2600(22)00006-6
Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415. doi:10.1056/NEJMoa2101643. Epub 2021 Jun 16.
Murugesan H, Cs G, Nasreen HS, Santhanam SMG, Ravi S, Es SS. An evaluation of efficacy and safety of tofacitinib, a JAK inhibitor in the management of hospitalized patients with mild to moderate COVID-19 - an open-label randomized controlled study. J Assoc Physicians India. 2022;69(12):11-12.
Zhang X, Shang L, Fan G, et al. The efficacy and safety of Janus kinase inhibitors for patients with COVID-19: a living systematic review and meta-analysis. Front Med (Lausanne). 2022;27(8):800492. doi:10.3389/fmed.2021.800492
Levy G, Guglielmelli P, Langmuir P, Constantinescu S. JAK inhibitors and COVID-19. J Immunother Cancer. 2022;10(4):e002838.
Simera I, Moher D, Hoey J, Schulz KF, Altman DG. A catalogue of reporting guidelines for health research. Eur J Clin Invest. 2010;40(1):35-53.
Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. National Science Review. 2020;7(6):998-1002.
RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645.
Sarhan RM, Harb HS, Abou Warda AE, et al. Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 patients. J Infect Public Health. 2022;15(1):116-122.
Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270.
Pomponio G, Ferrarini A, Bonifazi M, et al. Tocilizumab in COVID-19 interstitial pneumonia. J Intern Med. 2021;289(5):738-746.
Nystrom SE, Li G, Datta S, et al. JAK inhibitor blocks COVID-19-cytokine-induced JAK-STAT-APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022;26:e157432.
Zhang Y, Gargan S, Roche FM, Frieman M, Stevenson NJ. Inhibition of the IFN-α JAK/STAT pathway by MERS-CoV and SARS-CoV-1 proteins in human epithelial cells. Viruses. 2022;14(4):667.
Abizanda P, Calbo Mayo JM, Mas Romero M, et al. Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia. J Am Geriatr Soc. 2021;69(10):2752-2758.
Akbarzadeh-Khiavi M, Torabi M, Rahbarnia L, Safary A. Baricitinib combination therapy: a narrative review of repurposed Janus kinase inhibitor against severe SARS-CoV-2 infection. Infection. 2022;50(2):295-308.
Moreno-González G, Mussetti A, Albasanz-Puig A, et al. A phase I/II clinical trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: a structured summary of a study protocol for a randomised controlled trial. Trials. 2021;22(1):116.
Guschin D, Rogers N, Briscoe J, et al. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995;14(7):1421-1429. doi:10.1002/j.1460-2075.1995.tb07128.x.
Rodig SJ, Meraz MA, White JM, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93(3):373-383. doi:10.1016/s0092-8674(00)81166-6
Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234-4243.
Boutron I, Chaimani A, Meerpohl JJ, et al. The COVID-NMA project: building an evidence ecosystem for the COVID-19 pandemic. Ann Intern Med. 2020;173(12):1015-1017. doi:10.7326/M20-5261
https://covid-nma.com/
Mueller RB, Schulze-Koops H, Furst DE, et al. Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheumatoid arthritis: a post hoc analysis of an open-label, long-term extension study (ORAL sequel). Clin Rheumatol. 2022;41(4):1045-1055.
Burmester GR, Nash P, Sands BE, et al. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure. RMD Open. 2021;7(2):e001595.
Ytterberg SR, Bhatt DL, Mikuls TR, et al. ORAL surveillance investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326.
Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18(5):301-304.
Agarwal A, Rochwerg B, Lamontagne F, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;4(370):m3379. doi:10.1136/bmj.m3379
Agenzia Italiana del Farmaco (AIFA). https://www.aifa.gov.it/-/utilizzo-di-tocilizumab-per-la-terapia-dei-pazienti-affetti-da-covid-19