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Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019The GRECCO-19 Randomized Clinical Trial

Educational Objective
To understand the affects and clinical outcomes of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers in Patients with COVID-19
1 Credit CME
Key Points

Question  Is the receipt of colchicine among patients hospitalized with symptomatic coronavirus disease 2019 associated with clinical benefit?

Findings  In this randomized clinical trial of 105 patients, the rate of the primary clinical end point (clinical deterioration) was higher in the control group than in the colchicine group, and the time to clinical deterioration was shorter in the control group than in the colchicine arm. No difference was observed in the primary biochemical end point (high-sensitivity troponin concentration), but patients in the colchicine group had a smaller increase in dimerized plasma fragment D compared with patients in the control group.

Meaning  The hypothesis-generating findings of this study suggest a role for colchicine in the treatment of patients with coronavirus disease 2019.

Abstract

Importance  Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile.

Objective  To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19).

Design, Setting, and Participants  In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece.

Intervention  Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks.

Main Outcomes and Measures  Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis.

Results  A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003).

Conclusions and Relevance  In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution.

Trial Registration  ClinicalTrials.gov Identifier: NCT04326790

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Article Information

Accepted for Publication: May 29, 2020.

Published: June 24, 2020. doi:10.1001/jamanetworkopen.2020.13136

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Deftereos SG et al. JAMA Network Open.

Corresponding Author: Spyridon G. Deftereos, MD, PhD, Second Department of Cardiology, Attikon Hospital, National and Kapodistrian University of Athens, Greece, 1 Rimini St, Chaidari, Attiki, Greece (spdeftereos@gmail.com).

Author Contributions: Dr Deftereos had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Deftereos, Giannopoulos, Vrachatis, Siasos, Giotaki, Gargalianos, Sianos, Sipsas, Gogos, Olympios, Migdalis, Angelidis, Alexopoulos, Davlouros, Hahalis, Kanonidis, Kolettis, Pyrgakis, Toutouzas, Triposkiadis, Tsioufis, Vavouranakis, Reimers, Cleman, Goudevenos, Tsiodras, Tousoulis, Iliodromitis, Stefanadis.

Acquisition, analysis, or interpretation of data: Deftereos, Giannopoulos, Vrachatis, Giotaki, Gargalianos, Metallidis, Baltagiannis, Panagopoulos, Dolianitis, Randou, Syrigos, Kotanidou, Koulouris, Milionis, Tsoukalas, Tsagalou, Migdalis, Gerakari, Davlouros, Kanonidis, Katritsis, Manolis, Michalis, Naka, Martinez-Dolz, Reimers, Stefanini, Mehran, Dangas, Stefanadis.

Drafting of the manuscript: Deftereos, Giannopoulos, Vrachatis, Siasos, Giotaki, Gargalianos, Baltagiannis, Randou, Koulouris, Tsoukalas, Migdalis, Toutouzas, Vavouranakis, Reimers, Cleman.

Critical revision of the manuscript for important intellectual content: Deftereos, Vrachatis, Giotaki, Gargalianos, Metallidis, Sianos, Panagopoulos, Dolianitis, Syrigos, Kotanidou, Milionis, Sipsas, Gogos, Olympios, Tsagalou, Migdalis, Gerakari, Angelidis, Alexopoulos, Davlouros, Hahalis, Kanonidis, Katritsis, Kolettis, Manolis, Michalis, Naka, Pyrgakis, Triposkiadis, Tsioufis, Martinez-Dolz, Reimers, Stefanini, Cleman, Goudevenos, Tsiodras, Tousoulis, Iliodromitis, Mehran, Dangas, Stefanadis.

Statistical analysis: Deftereos, Giannopoulos, Vrachatis, Baltagiannis, Vavouranakis.

Obtained funding: Deftereos, Migdalis.

Administrative, technical, or material support: Deftereos, Vrachatis, Gargalianos, Sianos, Baltagiannis, Syrigos, Kotanidou, Koulouris, Sipsas, Migdalis, Gerakari, Kolettis, Michalis, Iliodromitis.

Supervision: Deftereos, Giannopoulos, Siasos, Gargalianos, Syrigos, Gogos, Tsoukalas, Olympios, Alexopoulos, Hahalis, Kanonidis, Katritsis, Kolettis, Pyrgakis, Toutouzas, Reimers, Tsiodras, Iliodromitis, Mehran, Stefanadis.

Conflict of Interest Disclosures: Dr Vrachatis reported receiving a scholarship from Hellenic Society of Cardiology. Dr Michalis reported receiving grants and nonfinancial support from ELPEN Pharmaceuticals outside the submitted work. Dr Naka reported receiving grants and nonfinancial support from ELPEN Pharmaceuticals outside the submitted work. Dr Stefanini reported receiving a research grant to his institution and speaker fees from Boston Scientific and speaker fees from B. Braun Medical, Biosensors, and GADA outside the submitted work. Dr Mehran reported receiving grants and personal fees from Abbott Laboratories; grants from Applied Therapeutics, Bayer, Beth Israel Deaconess, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, and OrbusNeich; receiving grants from and serving on the advisory board of Bristol-Myers Squibb; receiving grants from and having a spouse who is a consultant for Abiomed; having a spouse who is a consultant for The Medicines Company; serving as a consultant for Boston Scientific, Janssen Scientific Affairs, Medscape/WebMD, Roivant Services, Sanofi, Siemens Medical Solutions, and Spectranetics/Philips/Volcano; receiving nonfinancial support from Idorsia Pharmaceuticals and Regeneron Pharmaceuticals; receiving advisory and speaking fees from Medtelligence (Janssen Scientific Affairs); serving on the data safety monitoring board for Watermark Research Partners; owning equity in Claret Medical and Elixir Medical; and serving as associate editor for ACC and JAMA Cardiology outside the submitted work. Dr Dangas reported receiving grants and personal fees from AstraZeneca, Janssen Pharmaceuticals, Sanofi, and Abbott Laboratories and receiving grants from Bayer, Daiichi-Sankyo, Bristol-Myers Squibb, and Novartis outside the submitted work. No other disclosures were reported.

Funding/Support: The study was funded by ELPEN Pharmaceuticals, Acarpia Pharmaceuticals, and Karian Pharmaceuticals.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The GRECCO-19 investigators comprises George Adamis, MD (First Department of Internal Medicine, G. Gennimatas General Hospital of Athens, Athens, Greece); Alexandra Agorogianni, MD (Second Medical Department, NIMTS Hospital, Athens, Greece); Evangelos Balis, MD (First Intensive Care Unit, General Hospital Evangelismos, National and Kapodistrian University of Athens, Athens, Greece); Ioannis Baraboutis, MD (Department of Internal Medicine, Pammakaristos Hospital, Athens, Greece); Zafeiria Barmparessou, MD (First Department of Pneumonology, General Hospital Sotiria, National and Kapodistrian University of Athens, Athens, Greece); Georgios Bobotis, MD (Department of Cardiology, Papagerogiou Hospital); George Bouras, MD (Cardiology Department, NIMTS Hospital); Alexandra Chronaiou, MD (Fourth Department of Pneumonology, General Hospital Sotiria); Theofilos Chrysanthidis, MD (First Department of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece), Ioanna Davoni, RN (Department of Cardiology, G. Gennimatas General Hospital of Athens); Gerasimos Deftereos, BSc (Department of Cardiology, G. Gennimatas General Hospital of Athens); Evangelos Oikonomou, MD (First Department of Cardiology, Hippokration Hospital, National and Kapodistrian University of Athens, Greece); Nadia El Fellah, MD (Department of Internal Medicine, General Hospital of West Attica Agia Varvara, Athens, Greece); Dimitrios Filippou, MD (Department of Anatomy, National and Kapodistrian University of Athens); Katerina Fountoulaki, MD (Department of Cardiology, General Hospital of Elefsina Thriasio, Elefsina, Greece); Paraskevi C. Fragkou, MD (Fourth Department of Internal Medicine, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece); Maria Giaka, MD (Department of Internal Medicine, General Hospital of Kozani, Kozani, Greece); Sotirios Giotakis, MD (Second Department of Cardiology, Attikon Hospital), Konstantina Goula, RN (Department of Cardiology, G. Gennimatas General Hospital of Athens); Sotiria Grigoropoulou, MD (Fourth Department of Internal Medicine, Attikon Hospital); Konstantinos Iliodromitis, MD (Second Department of Cardiology, Attikon Hospital); Edison Jahaj, MD (First Intensive Care Unit, General Hospital Evangelismos); George Kalambokis, MD (First Department of Internal Medicine, Ioannina University Hospital, University of Ioannina, Ioannina, Greece); Andreas Kaoukis, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Drosos E. Karageorgopoulos, MD (Fourth Department of Internal Medicine, Attikon Hospital); Nikolaos Karamvakalis, MD (Second Medical Department, NIMTS Hospital); Stratis Katsianos, MD (Third Department of Cardiology, General Hospital Sotiria); Vasilios Kekeris, MD (Airport Services of Emergency Medical Care/EKAB); George Kochiadakis, MD (Cardiology Department, University of Crete, Heraclion, Greece); Anastasios Kollias, MD (Third Department of Internal Medicine, General Hospital Sotiria); Fotios Kolokathis, MD (Second Department of Cardiology, Attikon Hospital); Michalis Komis, MD (Department of Cardiology, General Hospital of Elefsina Thriasio); Athanasios Koromilias, MD (First Department of Pneumonology, General Hospital Sotiria); Charalampos Kossyvakis, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Ioanna Kotsamidi, MD (Department of Internal Medicine, General Hospital of Kozani); Eleanna Kotsia, MD (Second Department of Cardiology, Attikon Hospital); Artemis Kyriakidou, MD (Department of Internal Medicine, General Hospital of Kastoria, Kastoria, Greece); Konstantinos G. Kyriakoulis, MD (Third Department of Internal Medicine, General Hospital Sotiria); Sotiria Laparidou, MD (Department of Internal Medicine, General Hospital of Kozani); Fotios Lezgidis, MD (Department of Internal Medicine, Mpodosakio General Hospital of Ptolemaida, Ptolemaida, Greece); Georgia Loli, MD (First Department of Internal Medicine, AHEPA Hospital); Spyridon P. Louvros, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Theodora Maniatopoulou, MD (First Department of Internal Medicine, Ioannina University Hospital); Anastasia Mavrogiannaki, MD (Second Medical Department, NIMTS Hospital); Eirini Melidou, MD (Department of Internal Medicine, General Hospital of Kozani); Nikolaos Moussas, MD (Athens Medical Center, Athens, Greece); Danai Mparlampa, MD (Department of Internal Medicine, Pammakaristos Hospital); George Neroutsos, MD (Department of Cardiology, Chalkida General Hospital, Chalkida, Greece); Anastasia Nikolaidou, MD (First Department of Internal Medicine, AHEPA Hospital); Sebastien-Filippas Ntekouan, MD (First Department of Internal Medicine, Ioannina University Hospital); Dimitrios Ntemos, MD (Department of Internal Medicine, General Hospital of Kozani); Dimitrios Palaiologos, MD (Second Department of Cardiology, Attikon Hospital); Aikaterini Panteli, MD (First Department of Internal Medicine, Ioannina University Hospital); Konstantinos Papathanasiou, MD (Second Department of Cardiology, Attikon Hospital); Fragkiskos Parthenakis, MD (Cardiology Department, University of Crete); Sofia Pavlidou, MD (Department of Internal Medicine, Mpodosakio General Hospital of Ptolemaida); Vasilis Petrakis, MD (Second Department of Internal Medicine, General Hospital of Alexandroupoli, Democritus University of Thrace, Alexandroupoli, Greece); Garyphallia Poulakou, MD (Third Department of Internal Medicine, General Hospital Sotiria); Stefanos Poulios, MD (Department of Internal Medicine, General Hospital of Kozani), Konstantinos Raisakis, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Grigorios Salvaras, MD (Department of Internal Medicine, Mpodosakio General Hospital of Ptolemaida), John Skoularigis, MD (Department of Cardiology, University of Thessaly, Larissa, Greece); Nikoleta Stanitsa, MD (Second Department of Cardiology, Attikon Hospital); Jorge Sanz-Sánchez, MD (Cardio Center, Humanitas Clinical and Research Hospital IRCCS, Rozzano-Milan, Italy); Eleni Sarri, MD (Second Department of Cardiology, Attikon Hospital); Anastasios Semertzidis, MD (Department of Internal Medicine, General Hospital of Kastoria); Ioannis Styliadis, MD (Department of Cardiology, Papagerogiou Hospital); Prodromos Temberikidis, MD (First Intensive Care Unit, General Hospital Evangelismos); Charalampos Thanos, MD (Department of Internal Medicine, Pammakaristos Hospital); Andreas Theodorakis, MD (Department of Cardiology, Missolonghi General Hospital, Missolonghi, Greece), Christos Tolis, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Dimitrios Touloumenidis, MD (Department of Internal Medicine, Mpodosakio General Hospital of Ptolemaida); Athanasios Trikas, MD (Cardiology Department, Elpis General Hospital, Athens, Greece); Olga Tsachouridou, MD (First Department of Internal Medicine, AHEPA Hospital); Dimitrios Tsiachris, MD (Athens Medical Center); Ilias Tsiakas, MD (First Department of Internal Medicine, Ioannina University Hospital); Panagiotis-Anastasios Tsioufis, MD (Department of Internal Medicine, General Hospital of Kozani); George Tsitsinakis, MD (Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Hospital, Milan, Italy); Stamatios D. Tsouroulas, MD (Department of Cardiology, G. Gennimatas General Hospital of Athens); Argyris Tzouvelekis, MD (First Department of Pneumonology, General Hospital Sotiria); Ioannis Vagias, MD (Department of Internal Medicine, General Hospital of Kozani); Panagiotis Xarras, MD (Department of Internal Medicine, General Hospital of Kozani); Alexandra Yannou, MD (Department of Internal Medicine, Pammakaristos Hospital); Dimitrios Yiagoulis, MD (Department of Internal Medicine, Mpodosakio General Hospital of Ptolemaida).

Data Sharing Statement: See Supplement 3.

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