Colchicine Is Safe Though Ineffective in the Treatment of Severe COVID-19: a Randomized Clinical Trial (COLCHIVID)
MD Abdiel Absalón-Aguilar, MD Marina Rull-Gabayet, MD Alfredo Pérez-Fragoso, PhD Nancy R Mejía-Domínguez, PhD Carlos Núñez-Álvarez, MD, PhD David Kershenobich-Stalnikowitz, MD José Sifuentes-Osornio, MD Alfredo Ponce-De-León, MD, MSc Fernanda González-Lara, MD, MSc Eduardo Martín-Nares, MD Sharon Montesinos-Ramírez, MD Martha Ramírez-Alemón, MD Pamela Ramírez-Rangel, MD Manlio F Márquez, Juan Carlos Plata-Corona, Guillermo Juárez-Vega, MD, PhD Diana Gómez-Martín, MD, PhD Jiram Torres-Ruiz
Journal of General Internal Medicine, doi:10.1007/s11606-021-07203-8
BACKGROUND: Colchicine is an available, safe, and effective anti-inflammatory drug and has been suggested as a COVID-19 treatment, but its usefulness in hospitalized severe COVID-19 patients has not been thoroughly demonstrated.
OBJECTIVE: To address the safety and efficacy of colchicine in hospitalized patients with severe COVID-19.
DESIGN: We conducted a triple-blind parallel nonstratified placebo-controlled clinical trial.
PARTICIPANTS: We recruited 116 hospitalized patients with severe COVID-19 in Mexico.
INTERVENTIONS: Patients were randomized to receive 1.5 mg of colchicine or placebo at the time of the recruitment in the study (baseline) and 0.5 mg BID PO to complete 10 days of treatment.
MAIN MEASURES: The primary composite outcome was the progression to critical disease or death. Besides, we evaluated immunological features at baseline and after recovery or disease progression in 20 patients. KEY RESULTS: Fifty-six patients were allocated to colchicine and 60 patients received placebo. The study was suspended after the second interim analysis demonstrated colchicine had no effect on the primary outcome (OR 0.83, 95%CI 0.35-1.93, P = 0.67), nor in the days of ICU and hospital stays. Adverse events were similar between groups (OR 1.63, 95% CI 0.66-3.88, P = 0.37). After colchicine treatment, patients had higher BUN and lower serum levels of IL-8, IL-12p70, and IL-17A.
Declarations
Conflict of Interest The authors declare that they do not have a conflict of interest. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Apostolidou, Skendros, Kambas, Mitroulis, Konstantinidis et al., Neutrophil extracellular traps regulate IL-1beta-mediated inflammation in familial Mediterranean fever, Ann Rheum Dis,
doi:10.1136/annrheumdis-2014-205958.Barnes, Adrover, Baxter-Stoltzfus, Borczuk, Cools-Lartigue et al., Targeting potential drivers of COVID-19: Neutrophil extracellular traps, J Exp Med,
doi:10.1084/jem.20200652Borges, Pithon-Curi, Curi, Hatanaka, COVID-19 and Neutrophils: The Relationship between Hyperinflammation and Neutrophil Extracellular Traps, Mediators Inflamm,
doi:10.1155/2020/8829674.Brunetti, Diawara, Tsai, Firestein, Nahass et al., Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19, J Clin Med,
doi:10.3390/jcm9092961.Chalmers, Crichton, Goeminne, Cao, Humbert et al., Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline, Eur Respir J,
doi:10.1183/13993003.00048-2021Chi, Ge, Wu, Zhang, Wu et al., Serum Cytokine and Chemokine Profile in Relation to the Severity of Coronavirus Disease 2019 in China, J Infect Dis,
doi:10.1093/infdis/jiaa363.Cicco, Cicco, Racanelli, Vacca, Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment, Mediators Inflamm,
doi:10.1155/2020/7527953.Deftereos, Giannopoulos, Vrachatis, Siasos, Giotaki et al., Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2020.13136.Demidowich, Levine, Apps, Cheung, Chen et al., Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial, Int J Obes (Lond),
doi:10.1038/s41366-020-0598-3.Elshafei, El-Bardissy, Khalil, Danjuma, Mubasher et al., Colchicine use might be associated with lower mortality in COVID-19 patients: A meta-analysis, Eur J Clin Invest,
doi:10.1111/eci.13645Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in Hospitalized Patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2021436.Hariyanto, Halim, Jodhinata, Yanto, Kurniawan, Colchicine treatment can improve outcomes of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis, Clin Exp Pharmacol Physiol,
doi:10.1111/1440-1681.13488.Horby, Campbell, Spata, Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label
Kaiser, Leunig, Pekayvaz, Popp, Joppich et al., Self-sustaining interleukin-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19,
doi:10.1172/jci.insight.150862.Karatza, Ismailos, Karalis, Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens, Xenobiotica,
doi:10.1080/00498254.2021.1909782.Li, Zhang, Fang, Zhao, Qian et al., The prognostic value of IL-8 for the death of severe or critical patients with COVID-19, Medicine,
doi:10.1097/MD.0000000000023656.Liu, Tao, Lei, Li, Kui et al., Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease, Chin Med J (Engl,
doi:10.1097/CM9.0000000000000775Lood, Blanco, Purmalek, Carmona-Rivera, Ravin et al., Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease, Nat Med,
doi:10.1038/nm.4027Lopes, Bonjorno, Giannini, Amaral, Menezes et al., Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial, RMD Open,
doi:10.1136/rmdopen-2020-001455Ma, Zhang, Ye, Chen, Yu et al., High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19, Front Immunol,
doi:10.3389/fimmu.2021.626235.Manenti, Maggiore, Fiaccadori, Meschi, Antoni et al., Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study, PLoS One,
doi:10.1371/journal.pone.0248276.Misra, Gasparyan, Zimba, Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates, Rheumatol Int,
doi:10.1007/s00296-020-04694-2.Nawangsih, Kusmala, Rakhmat, Handayani, Juliastuti et al., Colchicine and mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia: A systematic review, meta-analysis, and meta-regression, Int Immunopharmacol,
doi:10.1016/j.intimp.2021.107723.Olivas-Martinez, Jimenez, Lozano-Cruz, Ortiz-Brizuela, Tovar-Mendez, In-hospital mortality from severe COVID-19 in a tertiary care center in Mexico City; causes of death, risk factors and the impact of hospital saturation, PLoS One,
doi:10.1371/journal.pone.0245772Ong, Fong, Young, Chan, Lee et al., Persistent Symptoms and Association With Inflammatory Cytokine Signatures in Recovered Coronavirus Disease 2019 Patients, Open Forum Infect Dis,
doi:10.1093/ofid/ofab156.Panigada, Bottino, Tagliabue, Grasselli, Novembrino et al., Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis, J Thromb Haemost,
doi:10.1111/jth.14850Peter, Sandeep, Rao, Kalpana, Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19, Front Pharmacol,
doi:10.3389/fphar.2020.583777.Pisaniello, Fisher, Farquhar, Vargas-Santos, Hill et al., Efficacy and safety of gout flare prophylaxis and therapy use in people with chronic kidney disease: a Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-initiated literature review, Arthritis Res Ther,
doi:10.1186/s13075-021-02416-y.Raucci, Mansour, Casillo, Saviano, Caso et al., Interleukin-17A (IL-17A), a key molecule of innate and adaptive immunity, and its potential involvement in COVID-19-related thrombotic and vascular mechanisms, Autoimmun Rev,
doi:10.1016/j.autrev.2020.102572.Reyes, Hu, Teperman, Wampler Muskardin, Tardif et al., Anti-inflammatory therapy for COVID-19 infection: the case for colchicine, Ann Rheum Dis,
doi:10.1136/annrheumdis-2020-219174Sandhu, Tieng, Chilimuri, Franchin, A Case Control Study to Evaluate the Impact of Colchicine on Patients Admitted to the Hospital with Moderate to Severe COVID-19 Infection, Can J Infect Dis Med Microbiol,
doi:10.1155/2020/8865954Scarsi, Piantoni, Colombo, Airo, Richini et al., Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome, Ann Rheum Dis,
doi:10.1136/annrheumdis-2020-217712.Siemieniuk, Bartoszko, Ge, Zeraatkar, Izcovich et al., Drug treatments for covid-19: living systematic review and network meta-analysis, BMJ,
doi:10.1136/bmj.m2980.Tardif, Bouabdallaoui, Allier, Gaudet, Shah et al., Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial, Lancet Respir Med,
doi:10.1016/S2213-2600(21)00222-8.Vrachatis, Giannopoulos, Giotaki, Raisakis, Kossyvakis et al., Impact of colchicine on mortality in patients with COVID-19: A meta-analysis, Hellenic J Cardiol,
doi:10.1016/j.hjc.2020.11.012.Yue, Liang, Gu, Zhao, Zhang et al., Comparative transcriptome analysis to elucidate the therapeutic mechanism of colchicine against atrial fibrillation, Biomed Pharmacother,
doi:10.1016/j.biopha.2019.109422.Zhao, Qin, Zhang, Li, Liang et al., Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease, JCI Insight,
doi:10.1172/jci.insight.139834
