Anti-inflammatory therapy for COVID-19 infection: the case

1Reyes AZ, et al. Ann Rheum Dis 2020;0:1–8. doi:10.1136/annrheumdis-2020-219174

Review

Anti- inflammatory therapy for COVID-19 infection: the case for colchicineAaron Z Reyes ,1 Kelly A Hu,1 Jacob Teperman,1 Theresa L Wampler Muskardin,2,3 Jean- Claude Tardif,4 Binita Shah,5,6 Michael H Pillinger3,7

To cite: Reyes AZ, Hu KA, Teperman J, et al. Ann Rheum Dis Epub ahead of print: [please include Day Month Year]. doi:10.1136/annrheumdis-2020-219174

Handling editor Josef S Smolen

► Additional material is published online only. To view, please visit the journal online (http:// dx. doi. org/ 10. 1136/ annrheumdis- 2020- 219174).

For numbered affiliations see end of article.

Correspondence toDr Michael H Pillinger, Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Michael. Pillinger@ nyulangone. org

AZR, KAH and JT are joint first authors.BS and MHP are joint senior authors.

Received 23 September 2020Revised 9 November 2020Accepted 27 November 2020

© Author(s) (or their employer(s)) 2020. No commercial re- use. See rights and permissions. Published by BMJ.

ABSTRACTThe search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS- CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti- inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS- CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front- line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource- replete and resource- poor regions.

INTRODUCTIONAs of 27 October 2020, almost 1 year after the first reported cases, the SARS- CoV-2 had resulted in over 43 million people infected and over 1.1 million deaths from COVID-19 worldwide.1 Clin-ical experience and data underline the role of exces-sive inflammation in the pathophysiology of the disease and suggest a potential role for colchicine, a drug with pleiotropic effects.

BIOLOGY OF COVID-19: THE ROLE OF INFLAMMATIONCOVID-19 progression can be divided into three distinct phases (figure 1) including: (1) early infec-tion phase, wherein the virus infiltrates host cells in the lung parenchyma; (2) pulmonary phase, in which viral propagation causes lung tissue injury as the host immune response is activated and (3) the inflammatory cascade, which is triggered by pathogen- associated molecular patterns (ie, viral RNA) and damage- associated molecular patterns (DAMPs, ie, cellular debris released during pyro-ptosis) exposed during active viral replication and release. This third phase of the inflammatory cascade may occur even as viral titers are falling and is comprised of components targeted by colchicine (activation of the inflammasome that drives the cytokine storm, activation of neutro-phils and the neutrophil/thrombosis interface)2 (figure 2).

Activation of the inflammasomeSignals driven by SARS- CoV-2 act on macrophages and other myeloid cells to drive assembly of a proin-flammatory protein complex, the nod- like receptor protein 3 (NLRP3) inflammasome,3 composed of NLRP3, apoptosis- associated speck- like protein adaptor and cysteine- dependent aspartate- directed protease-1 (caspase-1).4 Activated caspase-1 activity then converts the precursors pro- interleukin (IL)-1β and pro- IL-18 to their active forms. Addi-tionally, caspase-1 activates Gasdermin- D, forming pores in the cell membrane permitting large- scale secretion of IL-1β that, among other actions, induces macrophages to release large quantities of additional proinflammatory cytokines.5 6 IL-1β, tumour necrosis factor (TNF) and ligation of toll- like receptors activate NF-κB3 and further upregu-late the inflammasome. IL-1β and other cytokines additionally recruit large numbers of leukocytes from the marrow, which in turn undergo activation and cytokine production in an accelerating spiral. In the related SARS- CoV-1, a small envelope (E) protein augments this reaction by self- assembling into an ion channel within the host cell membrane, causing calcium dysregulation that promotes further assembly and activation of the NLRP3 inflammasome.7 More study is needed to determine if the E protein of SARS- CoV-2 has a similar effect on the inflammasome.

The production of IL-1β drives the synthesis of IL-6, a cytokine that induces C reactive protein (CRP) and has been especially implicated as a major proinflammatory agent in the COVID-19 cytokine storm.8–11

Activation of neutrophilsCytokines including IL-1β and IL-6 prime neutro-phils for activation by chemoattractants and upregu-late intercellular adhesion molecules on endothelial cells. The resulting neutrophil adhesion to the vascu-lature promotes neutrophil diapedesis and infil-tration into the affected tissues—in COVID-19 infection, initially into lung parenchyma, but later into other organs. Once neutrophils migrate to sites of inflamed tissue, they degranulate and release proinflammatory cytokines and chemokines, prote-ases, antiviral proteins and toxic oxygen radicals. In the myocardium, neutrophils -play a prominent role in the development of myocarditis and cardio-genic shock.12–14

Neutrophil/thrombosis interfaceNeutrophils trigger a cascade of events in arteries that promote plaque destabilisation/rupture and

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2 Reyes AZ, et al. Ann Rheum Dis 2020;0:1–8. doi:10.1136/annrheumdis-2020-219174

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thrombosis.15–18 Neutrophils release the serine protease neutro-phil elastase, which inhibits tissue factor pathway inhibitor and leads to generation of thrombin, the most potent activator of platelets. Neutrophil extracellular traps provide a platform to activate coagulation via active neutrophil elastase adherent to extracellular neutrophil DNA.19 20 Activated neutrophils and other leukocytes also aggregate with platelets directly to further exacerbate inflammothrombosis.21–23 24 In the setting of extreme

inflammatory states, activated neutrophils adhere directly to each other (leukoaggregation), producing effective but usually transient vascular occlusions.25 Finally, neutrophils contribute to thrombosis via cytokine- induced release of α-defensin from neutrophil granules.26 27 Murine studies suggest that α-defensin, at concentrations similar to those observed in inflammatory conditions, results in accelerated, larger and denser thrombus formation.28 29 Human data suggest that patients with COVID-19

Figure 1 Model of COVID-19 severity. IL, interleukin.

Figure 2 Proposed pathophysiology of acute vascular inflammation in SARS- CoV-2 viral illness and potential therapeutic targets of colchicine. (A) Macrophage- driven inflammation leads to inflammasome activity, cytokine production and endothelial and neutrophil activation, with surface expression of selectins, integrins and intercellular adhesion molecules promoting neutrophil adhesion to the vasculature. Colchicine inhibits E- selectin and L- selectin expression on neutrophil and endothelial surfaces. (B) Neutrophils migrate through the endothelium following chemoattractant gradients. Colchicine impairs the rheologic properties of the neutrophil cytoskeleton, limiting theirability to transmigrate. (C) Inflammasome- generated cytokines, including IL-1β and IL-6, drive additional macrophage activation and cytokine production, in an accelerating pattern known as a cytokine storm. Colchicine inhibits the NLRP3 inflammasome, with the potential to prevent the development of cytokine storm. (D) Neutrophil activation releases neutrophil elastase, which inhibits tissue factor pathway inhibitor. Diminished tissue factor pathway inhibitor activity, along with endothelial injury, promote thrombin generation and platelet activation. In addition, neutrophils release α-defensin, associated with larger and more extensive thrombi. Colchicine inhibits neutrophil elastase and α-defensin release. (E) Neutrophils interact with platelets to form aggregates that are a feature of thrombosis. Colchicine decreases neutrophil- platelet aggregation. CRP, C reactive protein; IL, interleukin; NLRP3, nod- like receptor protein 3; TNF, tumour necrosis factor.



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infection have elevated levels of serum α-defensin proportional to COVID-19 disease severity.30

Clinical implicationsThe connections between inflammation, thrombosis and poor COVID-19 outcomes are well established. On admis-sion, patients from our own institution who were admitted to regular floors but subsequently transferred to the intensive care unit (ICU) had higher CRP concentrations (159±86 mg/L) than patients admitted to the regular floors overall (114±81 mg/L). On transfer to the ICU, CRP concentrations (184 mg/L±104) were higher still (unpublished, figure 3). Manifesta-tions of profound inflammation in severe COVID-19 include acute respiratory distress syndrome and distributive shock.14 15 17 Myocardial injury due to acute coronary syndrome (type 1) and/or supply- demand mismatch in the setting of profound inflam-matory response and haemodynamic changes (type 2) is also significantly greater in those with severe COVID-19.31 Vascular inflammation is associated with a large burden of both venous (deep venous thrombosis, pulmonary embolism) and arterial (myocardial infarction, stroke) thrombus.

Severe COVID-19 has also been characterised by extrapulmo-nary and extravascular manifestations. Acute kidney injury may be a result of direct inflammatory injury, given evidence of acute tubular necrosis with lymphocyte and macrophage infiltration of the tubulointerstitium on histopathology.32 The mechanism(s) of COVID- related hepatic injury remains unclear but preliminary studies suggest that the ACE2 receptor is preferentially expressed in cholangiocytes, suggesting that liver involvement may require

direct SARS- CoV-2 infection and injury of cholangiocytes.33 34 Cytokine storm itself can drive multisystem organ injury overall.

Together, these observations suggest that an anti- inflammatory agent with limited immunosuppressive potential could prove useful in preventing severe inflammatory injury and promoting improved patient outcomes.

COLCHICINEHistorical perspectiveAlthough colchicine first received approval from the US Food and Drug Administration in 2009, its modern use dates back two centuries. Indeed, papyri dating from 1500 BC describe the use of colchicine’s source plant—Colchicum autumnale—for pain and inflammation, making colchicine one of the world’s oldest anti- inflammatory therapeutics.35 Currently, colchicine is approved for treating and preventing acute gout and familial Mediterranean fever, and is used off label in Behçet’s disease, pericarditis and other inflammatory conditions.36

Colchicine and microtubules: inhibition of neutrophil activityMicrotubules are dynamic proteins that form via polymerisation of α-/β-tubulin dimers. Colchicine irreversibly intercalates into free α/β dimers that incorporate into and block microtubule extension.37 During inflammation, microtubules facilitate the movement of adhesion molecules onto cell surfaces. Colchicine concentrations are much higher in neutrophils than other leuko-cytes due to diminished activity of the P- glycoprotein membrane efflux pump that serves as an energy- dependent colchicine efflux

Figure 3 Markers of inflammation and thrombosis in patients admitted to the hospital for COVID-19. Admission inflammatory markers were obtained for all patients admitted to the regular (non- ICU) floors of NYU Langone Hospital for the first weeks (March–April 2020) of the COVID-19 pandemic surge in New York City. Among patients admitted to the regular floors, those who were subsequently transferred to the intensive care unit (ICU) had higher C reactive protein (CRP) levels than the group overall; among those transferred to the ICU, both CRP and D- dimer levels in the ICU were increased compared with prior to transfer, indicating that a worsening inflammatory state is a feature of more severe disease. Not shown in the figure: individuals admitted to the regular floors who were subsequently transferred to directly to the ICU also had higher ferritin levels than the non- ICU group overall (1452 vs 1178 mg/dL), and their mean ferritin level was found to be increased further on transfer to the ICU (1876 mg/dL).



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transporter.38 Thus, neutrophils appear to be more sensitive than other cells to lower serum concentrations of colchicine. Cronstein et al demonstrated that colchicine causes a quantitative decrease in leucocyte (L)- selectin expression and diminishes qualitative expression of endothelial (E)- selectin, two proteins involved in rolling and adhesion of neutrophils on endothelium.39 Disrup-tion of microtubules also inhibits neutrophil rheologic capacity, inhibiting their transmigration out of blood vessels.40

Additional studies show that colchicine directly inhibits intra-cellular neutrophil signalling and lysosomal enzyme release

during phagocytosis. Colchicine- mediated inhibition of chemo-attractant release (eg, leukotriene B4) suppresses neutrophil adhesion to inflamed endothelium.41 Colchicine also inhibits calcium influx, which raises intracellular cyclic adenosine mono-phosphate (cAMP) levels and dampens neutrophil responses.42 In lipopolysachharide- stimulated neutrophils, we observed that colchicine can dampen stimulated neutrophil metabolism as measured by extracellular acidification (unpublished, figure 4).

Colchicine and the inflammasome: inhibition of IL-1β and prevention of the cytokine stormMore recently, colchicine has been shown to decrease cyto-kine production by inhibiting activation of the NLRP3 inflam-masome (figure 5). The mechanism(s) of colchicine’s action on the inflammasome remain an area of ongoing investigation.43 44 Colchicine’s interruption of inflammasome activation reduces IL-1β production, which in turn prevents the induction of IL-6 and TNF and the recruitment of additional neutrophils and macrophages.45 46 Whereas the effect of specific anti- IL-6 inhibi-tion for COVID-19 treatment is somewhat controversial (online supplemental text 1), the ability of colchicine to affect multiple cytokines may offer unique advantages.

Colchicine and the Inflammation/thrombosis interfaceMurine models show that colchicine inhibits neutrophil release of α-defensin, thereby potentially preventing large thrombus burdens.29 47 At supratherapeutic concentrations, colchicine, through its microtubule effects, converts normal discoid plate-lets to rounded, irregular structures and inhibits platelet activa-tion by decreasing calcium entry.48 These mechanisms diminish in vitro platelet- to- platelet aggregation. In contrast, we demon-strated that standard clinical doses of colchicine do not decrease platelet- to- platelet aggregation but do diminish neutrophil- to- platelet aggregation,49 suggesting that colchicine at physiolog-ical doses may provide an inhibitory role at the inflammation/thrombosis interface without comprising homeostatic platelet- to- platelet function. Indeed, in vivo colchicine has not been shown to inhibit non- inflammatory- related thrombosis.

Adverse effects of colchicineColchicine metabolism occurs primarily inside hepatocytes via the cytochrome P450 3A4 (CYP3A4). Medications that strongly

Figure 4 Neutrophil metabolism in the presence of colchicine. Neutrophils were purified from healthy volunteer whole blood using the MACSxpress whole blood neutrophil isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and separated into four aliquots. Neutrophils were coincubated with and without lipopolysaccharide (LPS) and with and without colchicine. In vitro quantification of neutrophil metabolism, measured as extracellular acidification rate (ECAR) (mpH/min), was evaluated using a glycolysis stress test using a Seahorse XFe24 analyzer (Agilent Technologies, Santa Clara, California, USA). Using a modified assay, cells were first incubated with activators (LPS 10 ng/mL with or without colchicine 15 nM) for 10 min.

Figure 5 Colchicine inhibits inflammasome action and reduces supernatant levels of IL-1β. THP1 cells (macrophage cell line) were stimulated with monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals in the presence or absence of colchicine. Supernatants were analysed for IL-1β by Western blot. For the purposes of this figure, the original published blot was quantified using Image J. Adapted from Martinon et al.43



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inhibit CYP3A4 metabolism (eg, ritonavir, ketoconazole, clar-ithromycin, cyclosporine, diltiazem, verapamil) pose a risk of drug- drug interactions. A small number of publications report cases of death after coadministration of clarithromycin and colchicine in patients with severe chronic renal disease.50 51 Similar cases have been rarely reported in patients receiving atorvastatin, a statin that is also processed by CYP- 3A4, but not with statins that are not metabolised through CYP3A4. In a recent placebo- controlled randomised trial of 4745 patient with a recent myocardial infarction, patients receiving daily colchicine experienced no adverse effects related to the coad-ministration of statins, including atorvastatin.52 In another recent placebo- controlled randomised trial of 5522 patients with stable coronary artery disease, daily colchicine resulted in numerically higher rates of myalgia (HR 1.15, 95% CI 1.01 to 1.31) and one case of rhabdomyolysis (the patient made a full recovery).53 However, a non- significant trend towards increased non- cardiovascular death was observed that requires further investigation. Overall, reports of severe colchicine toxicity tend to occur in the setting of errors in colchicine prescribing.

Approximately 10%–20% of colchicine is excreted renally.36 However, dose reductions may only be necessary in patients with severe renal impairment.54 As a lipophilic molecule, colchi-cine is usually protein- bound in plasma, with P- glycoprotein in the intestinal lining serving as the primary protein for gut excretion of colchicine. Cyclosporine and ranolazine compete for the ligand site on P- glycoprotein and can therefore lead to delayed elimination. At higher concentrations for longer dura-tions, particularly in the setting of kidney disease, colchicine has been reported to occasionally induce a reversible neuromyop-athy. Acute overdose may cause multiorgan system failure and death. Furthermore, increased adverse events may be noted in the simultaneous presence of moderate renal insufficiency with use of multiple CYP3A4 inhibitors.

A meta- analysis of 35 randomised trials of colchicine versus placebo found that the most common and significant adverse effect was diarrhoea.55 56 The only other adverse effect that occurred at a greater frequency than placebo was a set of pooled gastrointestinal symptoms including nausea, vomiting, diar-rhoea, abdominal pain, loss of appetite, and bloating. A striking finding in this meta- analysis was the absence of increased infec-tion rates in the colchicine compared with the placebo arm. However, in contrast to most available data, one retrospective and one prospective study did report increased pneumonia risk with colchicine (online supplemental table 1).

COLCHICINE AND COVID-19: THE CLINICAL CASESeveral of the biological therapies that have been studied and/or used in the setting of severe SARS- CoV-2 infection target some of the same pathways as colchicine, including IL-1β (ie, anakinra) and IL-6 (ie, tocilizumab and sarilumab).57 Colchicine differs from these agents in having pleotropic mechanisms of action, being less potent on any single target, and being an oral agent. In contrast to the biological agents used in the midst of cyto-kine storm, colchicine is not immunosuppressive, is not known to increase risk of infection, and is inexpensive. A review of the mechanisms of SARS- CoV-2 and colchicine in parallel reveals a potential intervention point that may prevent the progression from inflammatory activation (phase 2) to a hyperinflammatory state (phase 3). Taken together with the clinical data described herein, the potential benefits of colchicine are suggested to be maximised when used early in the disease process (ideally prior to phase 2, but certainly prior to phase 3), such as in

non- hospitalised patients within a few days of diagnosis regard-less of symptoms and/or within a few days of hospitalisation if not already critically ill. However, the optimal timing continues to require further investigation.

Colchicine in non-rheumatological inflammatory conditionsMultiple randomised studies have evaluated the use of colchi-cine in non- rheumatologic inflammatory conditions. Two randomised trials in acute pericarditis demonstrated lower recurrence rate with colchicine versus conventional or placebo therapy.58 Colchicine reduced symptom persistence 72 hours after treatment initiation, and colchicine was beneficial even in the setting of recurrent pericarditis.59 Used after cardiac surgery, colchicine appears to prevent the inflammatory postpericar-diotomy syndrome.60

Colchicine may reduce risk of acute myocardial infarction (AMI). We demonstrated an association between daily colchi-cine use and decreased prevalence of AMI in patients with gout, a non- traditional cardiovascular risk factor.61 62 These findings were subsequently reproduced in an independent gout popula-tion.63 Two open- label prospective studies of daily colchicine use versus no colchicine use in patients with stable coronary artery disease already on aspirin and high- intensity statin therapy demonstrated a decrease in CRP levels with low- dose colchicine, and a significant reduction in cardiovascular events with daily colchicine vs no colchicine.64 65 The reduction in the primary clinical outcome was driven primarily by a reduction in AMI.65 The multicentre, double- blind COLchicine Cardiovascular Outcomes Trial (COLCOT) randomised 4745 patients within 30 days of AMI to colchicine or placebo and demonstrated a reduc-tion in the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, AMI, stroke or urgent revascularisa-tion with colchicine.52 The multicentre, double- blind Low Dose Colchicine 2 (LoDoCo 2) trial randomised 5522 patients with stable coronary artery disease and also demonstrated a reduc-tion in the primary composite endpoint of cardiovascular death, AMI, stroke or urgent revascularisation.53 Finally, in cases where the thrombus burden remains refractory to standard antiplatelet and anticoagulant therapies, colchicine has been shown to be associated with thrombus resolution.66

Our 400- patient randomised Colchicine in Percutaneous Coro-nary Intervention (Colchicine- PCI) trial demonstrated that when given as a standard loading dose prior to tissue injury (coronary stent placement), colchicine significantly dampened the upreg-ulation of IL-6 and CRP.67 These effects were observed 22–24 hours after the acute event, providing a rationale to administer colchicine earlier in the disease process to prevent clinical mani-festations of cytokine- induced injury. Consistent with a possible preventive role, colchicine is effective to prevent cytokine- based disease flares in gout and familial Mediterranean fever.45 Finally, colchicine has also been shown to dampen the inflammatory response and reduce CRP levels among subjects with metabolic syndrome.68 These data support the general anti- inflammatory effect of colchicine, independent of a specific disease state.

Colchicine trials in COVID-19The recent open- label, multicentre Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial in the UK demonstrated a reduction in 28- day mortality with dexamethasone (n=2104) vs usual care (n=4321) in patients hospitalised with severe COVID-19.69 These data support the principle that an anti- inflammatory strategy in COVID-19 may be helpful. However,



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glucocorticoids such as dexamethasone have intrinsic immuno-suppressive drawbacks that colchicine does not share.

Several early studies have evaluated the benefit of colchicine in COVID-19 patients. A retrospective single- centre study of 87 ICU patients with COVID-19 demonstrated a lower risk of death in patients on colchicine (adjusted HR 0.41, 95% CI 0.17 to 0.98).70 The Greek Effects of Colchicine in COVID-19 (GRECO-19) trial was the first prospective open- label randomised trial evaluating colchicine versus usual care in early hospitalised patients. This study of 105 patients found a signif-icant reduction in the primary clinical outcome of a two- point deterioration on WHO disease severity scale.71 The authors additionally noted suppression of D- dimer levels in the colchi-cine vs control group.71 An Italian study compared 122 hospi-talised patients who received colchicine plus standard- of- care (lopinavir/ritonavir, dexamethasone or hydroxychloroquine) with 140 hospitalised patients receiving standard- of- care alone. Colchicine had a significant mortality benefit (84% vs 64% survival) vs controls.72 A third prospective study randomised 38 hospitalised COVID-19 patients to colchicine or placebo in a double- blinded manner.73 Patients receiving colchicine had less need for supplemental oxygen at day 7 (6% vs 39%) and were more likely to be discharged at day 10 (94% vs 83%). Colchi-cine subjects also had greater reduction of CRP, and no increase in serious adverse events.73 Additional inpatient studies are ongoing (online supplemental table 2). Although the permitted use of other treatments could have biased the impact of colchi-cine in these studies, in the GRECO-19 trial no glucocorticoids were administered and other medications did not differ between the two groups; in the Italian study, there was no difference in outcomes among patients given colchicine who did or did not also receive dexamethasone.

Given its ease of use, tolerability and low cost, an argument for studying colchicine in the outpatient setting, to reduce hospi-talisation and adverse outcomes, may be even more compelling. Unfortunately, data on the use of colchicine in the setting of outpatient COVID-19 cases are sparse. In a very small case series from Italy, nine outpatients with COVID-19 were administered colchicine, of whom only one subject was ultimately hospital-ised. The hospitalised patient received 4 days of oxygen therapy and was discharged.74 Moreover, all patients experienced defer-vescence within 72 hours of colchicine initiation, suggesting an antipyretic effect. While these reports are insufficient to recom-mend colchicine for COVID-19 in clinical practice, they provide support for further study of colchicine in COVID-19, including in the outpatient setting. The ongoing ColCorona Trial ( www. colcorona. net) is a large placebo- controlled trial of colchicine use within 2 days of COVID-19 diagnosis, regardless of symp-toms, in patients with comorbidities that place patients at a higher risk of developing complications related to COVID-19 that may provide additional information.

CONCLUSIONSGiven the large body of data demonstrating colchicine’s inhibi-tory effects on neutrophil activity, cytokine generation and the inflammation/thrombosis interface, together with an overall lack of evidence for systemic immunosuppression, there is a ratio-nale to study colchicine as a potential treatment for COVID-19. Given that colchicine is generally well tolerated, simple to take and inexpensive, demonstration of colchicine as a useful agent in COVID-19 would potentially spare patients morbidity and mortality, help to conserve valuable clinical resources (hospital floor and ICU beds, ventilators, etc), and dramatically reduce the

cost of COVID-19 care. Colchicine might be of particular use in resource- poor rural and developing world settings, both of which have been increasingly affected by COVID-19. However, unless and until evidence is obtained from adequately designed and randomised placebo- controlled trials, this hypothesis must remain speculative.

The optimal dose of colchicine for daily use, even in well- established conditions such as gout, is unknown. Many but not all patients tolerate up to 1.2 mg daily in divided doses; whether lower doses such as 0.5 mg or less daily can be equally effective is unknown. The largest colchicine study for COVID-19 (ColCo-rona) is testing a dose of 0.5 mg daily based on prior cardiology trials. The duration of colchicine therapy for SARS- COV2 infec-tion would also need to be determined. Most studies to date test a treatment duration of 2–4 weeks, concordant with the acute course of the infection; whether a shorter or longer treatment would be optimal is unknown. Finally, the timing of colchicine initiation is uncertain, with some studies beginning treatment in the outpatient setting, and others in the early inpatient setting. Given the recent track record of failure of treatment of severe COVID-19 treatment with anti- IL-6 biologics such as tocili-zumab (a much more potent but also more specific immunosup-pressive agent), it is likely that the severe inpatient setting is not the optimal condition under which to assess colchicine efficacy.

Author affiliations1Internal Medicine, New York University Grossman School of Medicine, New York, New York, USA2Colton Center for Autoimmunity, Department of Medicine and Pathology, New York University School of Medicine, New York, New York, USA3Rheumatology/Medicine, New York University Grossman School of Medicine, New York, New York, USA4Montreal Heart Institute, Montreal, Québec, Canada5Cardiology/Medicine, New York University Grossman School of Medicine, New York, New York, USA6Cardiology/Medicine, VA New York Harbor Healthcare System, New York, New York, USA7Rheumatology/Medicine, VA New York Harbor Healthcare System, New York, New York, USA

Twitter Aaron Z Reyes @azrys

Contributors All authors contributed to conception or design of the work; and drafting the work or revising it critically for important intellectual content; and final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not- for- profit sectors.

Competing interests For the purposes of full disclosure, we note that BS receives support from the NIH/NHLBI (1R01HL146206, 3R01HL146206- 02S1) and VA ORD (iK2CX001074) for her work on colchicine in cardiovascular disease and COVID-19. J- CT reports grants and personal fees from Amarin, grants and personal fees from AstraZeneca, grants, personal fees and other from DalCor, grants from Esperion, grants from Ionis, grants and personal fees from Pfizer, grants and personal fees from Sanofi, grants and personal fees from Servier, personal fees from HLS Therapeutics, outside the submitted work; In addition, J- CT has a patent on pharmacogenomics- guided CETP inhibition issued, and a patent on the use of colchicine after myocardial infarction pending. MHP holds investigator- initiated grants from Horizon Therapeutics (to study urate deposition in the spines of gout patients) and Hikma Pharmaceuticals (to study the possible benefit of colchicine in knee osteoarthritis) and has served as a consultant for Horizon and Sobi. MHP also receives salary support from a CTSA award (1UL1TR001445) to New York University from the National Centre for the Advancement of Translational Science, National Institutes of Health. TLWM is supported by an NYU-HHC Clinical and Translational Science Institute KL2 grant and a Doris Duke Fund to Retain Clinical Scientists award. TLWM has served on an advisory board for Novartis and as a consultant to Regeneron, unrelated to this work

Patient consent for publication Not required.

Provenance and peer review Not commissioned; externally peer reviewed.



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ORCID iDAaron Z Reyes http:// orcid. org/ 0000- 0001- 5830- 8882

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Supplemental Text 1: IL-6 in COVID-19 Infection

The review by Leisman et al (2020) demonstrated IL-6 concentrations in other conditions associated with

markedly elevated cytokine levels (i.e., sepsis, CAR-T-associated cytokine release syndrome, and non-

COVID-19 ARDS) were anywhere from 12 to 100 times higher than the IL-6 concentrations associated

with severe or critical COVID-19 infection. The authors suggest that cytokine storm may not play as

pivotal a role in COVID-19-induced end-organ dysfunction as previously thought. However, it is

important to consider that these other hyperinflammatory conditions analyzed in the aforementioned have

differing pathophysiology and biology compared to COVID-19, and as such a head-to-head comparison

of IL-6 levels may not be entirely appropriate in evaluating the role of the cytokine response in COVID-

19. In fact, studies have shown that elevated IL-6 levels in COVID-19 are associated with higher SARS-

CoV-2 viral load and poorer prognosis, thus supporting the central role of a heightened inflammatory

response in COIVD-19 (1,2). This observation does not preclude the possibility that other cytokines

associated with the release syndrome (e.g., IL-1which is more directly regulated by colchicine than

IL6)) may be equally or more important than IL-6 in COVID-19 responses.

Since the start of the COVID-19 pandemic, significant resources have been allocated to investigate the

therapeutic efficacy of anti-IL-6 therapies with respect to severe COVID-19 infection. Thus far, the

results of these studies have been equivocal at best. In a meta-analysis by Lan et al, although patients

treated with tocilizumab were found to have lower all-cause mortality compared to the placebo group, the

results did not achieve statistical significance, with risk of ICU admission and the need for mechanical

ventilation similar between the two groups (3). None of the included studies were randomized controlled

trials, however, and in many of them baseline characteristics/illness severity of patients were not matched.

Larger-scale randomized trials have shown similar results, with trials of both tocilizumab and sarilumab

failing to meet their primary endpoint (4,5). Furthermore, some studies have demonstrated that the

immunosuppressive effects of anti-IL-6 therapies may actually contribute to adverse effects in COVID-19

patients due to secondary bacterial or, less commonly, fungal infections (3,6). Despite these overall

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis

doi: 10.1136/annrheumdis-2020-219174–8.:10 2020;Ann Rheum Dis, et al. Reyes AZ

disappointing results, ongoing studies continue to investigate anti-IL-6 agents with respect to combination

therapies, and alternative dosing regimens that may hold promise for COVID-19 infection.

Although colchicine has been shown to inhibit IL-6 secretion, it has multiple additional mechanisms of

action that may potentially temper the COVID-19-induced hyperinflammatory response. Additionally,

colchicine is not immunosuppressive compared to its anti-IL-6 counterparts, and thus may be a more

suitable COVID-19 treatment. Finally, most studies of colchicine have aimed to dampen inflammation at

an early stage, whereas most studies of anti-IL-6 therapeutics have been directed at treating the COVID-

19 inflammatory response at a very advance stage of the infection, when targeting a single cytokine may

simply be too little, too late.

References

1. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, Men D, Huang Q, Liu Y, Yang B, Ding J, Li F.

Detectable serum SARS-COV-2 viral load (RNAaemia) is closely correlated with drastically elevated

interleukin-6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis 2020; Epub ahead of print.

2. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, Jiang Y, Cheng X, Zhu

C, Xia Y. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 aree disease severity

predictors. Emerg Microbes Infect 2020;9(1):1123-1130.

3. Lan SH, Lai CC, Huang HT, Chhang SP, Lu LC, Hsueh PR. Tocilizumab for severe COVID-19: a

systematic review and meta-analysis. Int J Antimicrob Agents 2020; 56(3):106103.

4. Roche. Roche provides an update on the Phase III COVACTA trial of Actemra/RoActemra in

hospitalized patients with severe COVID-19 associated pneumonia. Available at:

https://www.roche.com/investors/updates/inv-update-2020-07029.htm. Accessed November 2, 2020.

5. Sanofi. Sanofi and Regeneron provide update on Kevzara (sarilumab) Phase 3 U.S. trial in COVID-19

patients. Available at: https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00.

Accessed November 2, 2020.

6. Kimmig LM, Wu D, Gold M, et al. IL-6 inhibition in critically ill COVID-19 patients is associated

with increased secondary infections. Preprint. medRxiv. 2020;2020.05.15.20103531. Published 2020 Sep

12.doi:10.1101/2020.05.15.20103531



https://www.roche.com/investors/updates/inv-update-2020-07029.htm

https://www.sanofi.com/en/media-room/press-releases/2020/2020-07-02-22-30-00

https://doi.org/10.1101/2020.05.15.20103531

Page 1

Supplemental Table 1. Studies Reporting the Risk of Pneumonia with Colchicine

Study Design Result

Nidorf et al, NEJM 2020

Prospective double-blind

trial, colchicine vs placebo

No increase in pneumonia in colchicine group

Tardif et al, NEJM 2020 Prospective double-blind

trial, colchicine vs placebo

Increased pneumonia in colchicine group

Besisow et al, European

Journal of Cardio-Thoracic

Surgery 2018

Prospective randomized

study, colchicine vs placebo

One patient with pneumonitis in colchicine

group vs none in placebo group

Tsai et al, Frontiers in

Pharmacology 2019

Retrospective cohort study,

colchicine vs no colchicine

Higher cumulative incidence of pneumonia in

colchicine group; higher with longer exposure

Spaetgens et al, Scientific

Reports 2017

Retrospective cohort study,

colchicine vs no colchicine

Increased pneumonia among past but not

current colchicine users



Page 1

Supplemental Table 2. Published and Ongoing Studies of Colchicine in COVID-19

eGFR – estimated glomerular filtration rate, QTc – corrected QT interval, CRP – c-reactive

protein, LDH – lactate dehydrogenase, IL-6 – interleukin-6, SARS – severe acute respiratory

syndrome, CK – creatinine kinase, CrCL – creatinine clearance, TNF-alpha – tumor necrosis

factor-alpha, GDF-15 – growth differentiation factor-15, BNP – B-type natriuretic peptide, IBD

– inflammatory bowel disease,

* Patients with hypersensitivity to colchicine, <18, and pregnant were not included in most

studies

Study (Date) Clinical

Setting

Design (n) Exclusion Criteria* Intervention Primary

Outcome(s)

Secondary

Outcome(s)

Significant

Results

Inflammatory

Measures

Reference

GRECCO-19

(April 3 to April 27, 2020)

Early

Inpatient

Randomized,

open-label vs

usual care

(105)

Hepatic failure, eGFR

<20 mL/min/1.73 m2,

QTc 450 ms, early

mechanical ventilation

Colchicine

1.5mg loading

dose + 0.5mg

after 60

minutes, then

0.5mg BID

1) maximum

high-sensitivity

cardiac troponin

level, 2) time for

CRP to reach

>3x ULN, 3)

Clinical

deterioration by

WHO scale

1) % requiring

mechanical ventilation,

2) all-cause mortality,

3) adverse events

Clinical primary

end point lower

(p=0.02),

Maximum D-

dimer lower

(p=0.04),

Higher diarrhea

incidence

(p=0.003)

CPK,

CRP,

d-dimer,

ferritin,

LDH,

procalcitonin,

troponin

Deftereos SG, Giannopoulos G, Vrachatis DA, 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.

2020;3(6):e2013136.

Scarsi et al.

(March 5 to April 5, 2020)

Early

Inpatient

Randomized,

open-label vs

usual care

(262)

Renal failure Colchicine 1mg

per day

(reduced to

0.5mg if severe

diarrhea)

Survival rates Clinical and laboratory

comparison

Higher survival

(84% vs 64%,

p<0.001)

CRP,

Ferritin

Scarsi M, Piantoni S, Colombo E, 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. 2020.

Lopes et al.

(April 11 to July 6, 2020)

Inpatient,

moderate

to severe

disease

Randomized,

double-blind,

placebo-

controlled

(38)

Weight 50 kg,

abnormal calcium or

potassium levels, QTc

450 ms, diarrhea

causing dehydration,

porphyria, myasthenia

gravis, uncontrolled

arrhythmia, metastatic

cancer,

immunosuppressive

chemotherapy,

CYP3A4 inhibitor use,

hepatic failure

Colchicine

0.5mg TID for

5 days, then

0.5mg BID for

5 days

1) Supplemental

oxygen, 2) LOS,

3) ICU

admission, 4)

ICU LOS, 5) all-

cause mortality

1) CRP, 2) LDH and

WBC relation, 3)

adverse events, 4) QT

interval >450 ms.

Less need for

supplemental

oxygen (p=0.01),

Shorter LOS

(p=0.01),

Reduction in

CRP (p<0.001)

CRP,

LDH

Lopes MIF, Bonjorno LP, Giannini

MC, et al. Beneficial effects of colchicine for moderate to severe

COVID-19: an interim analysis of a

randomized, double-blinded, placebo controlled clinical trial.

medRxiv. [Preprint]. Date

Accessed: August 25, 2020.

https://doi.org/10.1101/2020.08.06.20169573.



Page 2

Dalili et al.

(March 20, 2020 to

present)

Early

Inpatient

Randomized,

double-blind,

placebo-

controlled

(80, anticipated)

Hypoxia, hepatic

failure, eGFR < 20

mL/min/1.73 m2

Colchicine

1.5mg loading

dose, then

0.5mg BID

1) CRP change,

2) Clinical

deterioration by

WHO scale, 3)

PCR viral load

change, 4) CT

severity

LDH change Ongoing CRP,

LDH

ClinicalTrials.gov [Internet].

Tehran, Iran: National Library of

Medicine (US). 2020 April 24. Identifier NCT04360980. The

Effects of Standard Protocol With or

Without Colchicine in Covid-19 Infection; 2020 March 20 [cited

2020 August 26]. Available from:

https://clinicaltrials.gov/ct2/show/N

CT04360980.

Mostafaie et al.

(April 1, 2020 to present)

Inpatient Randomized,

double-blind,

placebo-

controlled

(200, anticipated)

Severe kidney

dysfunction

Colchicine plus

Phenolic

Monoterpene

Fractions

All-cause

mortality

1) Change in clinical

manigestation, 2) LOS,

3) Lab parameters

(CRP, Lymphocytes,

LDH, IL-6, ESR)

Ongoing CRP,

ESR

IL-6,

LDH


Kermanshah, Iran: National Library

of Medicine (US). 2020 May 18. Identifier NCT04392141.

Colchicine Plus Phenolic

Monoterpenes to Treat COVID-19;

2020 April 1 [cited 2020 August 26]. Available from:


CT04392141.

COLCOVID


Early or

Late

Inpatient

Randomized,

open-label vs

usual care

(2500,

anticipated)

No evidence of SARS Colchicine

1.5mg loading

dose, then

0.5mg 2 hours

later, then

0.5mg BID for

14 days or until

discharge

All-cause

mortality

Composite outcome:

mechanical ventilation

or death

Ongoing None ClinicalTrials.gov [Internet]. Santa Fe, Argentina: National Library of

Medicine (US). 2020 March 31.

Identifier NCT04328480. The ECLA PHRI COLCOVID Trial.

Effects of Colchicine on

Moderate/High-risk Hospitalized COVID-19 Patients. (COLCOVID);

2020 April 17 [cited 2020 August

26]. Available from:

https://clinicaltrials.gov/ct2/show/NCT04328480.

COLVID-19


Early

Inpatient

Randomized,

open-label vs

usual care

(308, anticipated)

Severe diarrhea, CrCL

< 30 mL/min, liver

damage, CYP3A4

inhibitor use,

tocilizumab use,

neutrophilia,

thrombocytopenia,

diverticulitis or bowel

perforation, ICU

admission

Colchicine

0.5mg TID for

30 days

Rate of entering

critical stage

1) WBC trend, 2)

SOFA change, 3) Lab

recovery (CK, ALT,

ferritin), Disease

remission, 4) Adverse

events

Ongoing CK,

ferritin

ClinicalTrials.gov [Internet]. Milan,

Italy: National Library of Medicine

(US). 2020 May 5. Identifier

NCT04375202. Colchicine in COVID-19: a Pilot Study

(COLVID-19); 2020 April 18 [cited

2020 August 26]. Available from:


ColCOVID-19



open-label vs

usual care

(310, anticipated)

Hypoxia, unstable,

hepatic failure,

antiviral use

Colchicine 1mg

daily

1) Clinical

improvement by

WHO, 2)

Discharge

1) Death, 2) Clinical

change by WHO, 3)

Mechanical

ventilation, 4) LOS, 5)

Time to mortality, 6)

Time to PCR negative,

7) Fever remission

time

Ongoing None ClinicalTrials.gov [Internet]. Parma,

Italy: National Library of Medicine

(US). 2020 March 26. Identifier

NCT04322565. Colchicine Counteracting Inflammation in

COVID-19 Pneumonia

(ColCOVID-19); 2020 April 20

[cited 2020 August 26]. Available

from:




Page 3

ACTCOVID19


Early

Outpatient

and Early

Inpatient

Randomized,

open-label

colchicine vs

IFN-beta vs ASA

vs rivaroxaban vs

usual care

(4000,

anticipated)

Advanced kidney

disease, advanced liver

disease, CYP3A4

inhibitor use,

therapeutic

anticoagulation or

antiplatelet use

Outpatient:

Colchicine

0.6mg BID for

3 days, then

0.6mg daily for

25 days.

Inpatient:

1.2mg loading

dose, then

0.6mg 2 hours

later, then

0.6mg BID for

28 days

Outpatient:

Composite

hospitalization or

death; Inpatient:

Composite:

mechanical

ventilation or

death

1) Clinical

deterioration by WHO,

2) Composite: MACE

Ongoing None ClinicalTrials.gov [Internet].

Ontario, Canada: National Library

of Medicine (US). 2020 March 27. Identifier NCT04324463. Anti-

Coronavirus Therapies to Prevent

Progression of Coronavirus Disease 2019 (COVID-19) Trial

(ACTCOVID19); 2020 April 21


from: https://clinicaltrials.gov/ct2/show/N

CT04324463.

COMBATCOVID19

(April 26 to June 14, 2020)


open-label vs

usual care

(70, anticipated)

Hypoxia using >8L

supplemental oxygen,

unstable, cirrhosis,

liver injury, CrCL < 30

mL/min, early

mechanical ventilation,


chemotherapy use

Colchicine

1.2mg loading

dose, then

0.6mg 2 hours

later, then

0.6mg BID for

14 days or until

discharge

% requiring

supplemental

oxygen >8L NC

1) Mechanical

ventilation, 2) LOS, 3)

Mortality, 4)

Maximum CRP, 5)

Maximum troponin

Pending

Publication

CRP,

troponin


Brooklyn, New York: National Library of Medicine (US). 2020

April 27. Identifier NCT04363437.

COlchicine in Moderate-severe Hospitalized Patients Before ARDS

to Treat COVID-19

(COMBATCOVID19); 2020 April

26 [cited 2020 August 26]. Available from:


CT04363437.

COL-COVID


Early

Inpatient

Randomized,

open-label vs

usual care

(102, anticipated)

Early mechanical

ventilation, IBD,

previous

neuromuscular disease,

< 1 year prognosis due

to other disease, eGFR

<30 mL/min, cirrhosis,

liver injury,

immunosuppressive or

immunomodulatory

use within 6 months

Colchicine

1mg, then

0.5mg 2 hours

later, then

0.5mg BID for

7 das, then

0.5mg daily for

28 days total

1) Clinical

deterioration by

WHO, 2) IL-6

changes

1) Clinical

improvement by WHO

scale, 2) SOFA

change, 3) NEWS

change, 4) Mechanical

ventilation time, 5)

Supplemental oxygen,

6) Lab changes (CRP,

TNF, GDF-15, IL-1β,

D-dimer, Leukocytes,

Lymphocytes,

Platelets, LDH,

Ferritin, Troponin,

BNP, PCR status), 7)

LOS, 8) ICU days, 9)

Mortality

Ongoing BNP,

CRP,

d-dimer,

GDF-15,

IL-1,

IL-6,

LDH,

TNF-alpha,

troponin


Murcia, Spain: National Library of Medicine (US). 2020 April 17.

Identifier NCT04350320. Trial to

Study the Benefit of Colchicine in

Patients With COVID-19 (COL-COVID); 2020 April 30 [cited 2020

August 26]. Available from:




Page 4

COLHEART-19

(May 1, 2020 to present)


open-label vs

usual care

150 (anticipated)

No cardiac injury,


severe hematologic

disorder, severe

neuromuscular

disorder, severe renal

impairment with

hepatic impairment

Colchicine

0.6mg BID for

30 days

Composite of all-

cause mortality,

mechanical

ventilation, or

mechanical

circulatory

support

1) Lab changes

(Troponin, BNP, CRP,

D-dimer), 2) LVEF

change, 3) Time to

primary endpoint, 4)

Number of mechanical

ventilation and

circulatory support, 5)

Rehospitalization, 6)

All-cause mortality

Ongoing BNP,

CRP,

d-dimer,

troponin

ClinicalTrials.gov [Internet]. Los

Angeles, California: National

Library of Medicine (US). 2020 April 21. Identifier NCT04355143.

Colchicine to Reduce Cardiac Injury

in COVID-19 (COLHEART-19); 2020 May 1 [cited 2020 August 26].

Available from:


CT04355143.

COLORIT

(May 8 to August 23,

2020)

Unspecifi

ed

Randomized,

open-label

3:1:1:3

(colchicine,

ruxolitinib,

secukinumab,

control)

(70, anticipated)

No hypoxia, normal

CRP, liver failure,

GFR < 20 mL/min,

QTc > 450 ms, steroid

or immunosuppressive

use, active cancer,

early mechanical

ventilation

Colchicine

0.5mg BID for

3 days, then

0.5mg

daily/BID

based on weight

for 7 days

Change from

baseline in CAS

COVID 19

1) Combination time

to death or mechanical

ventilation, 2) Lab

changes (CRP, D-

dimer), 3) EQ-5D

change, 4) Lung CT

exposure area change

Pending

Publication

CRP,

d-dimer


Moscow, Russia: National Library

of Medicine (US). 2020 May 27. Identifier NCT04403243.

COLchicine Versus Ruxolitinib and

Secukinumab In Open Prospective

Randomized Trial (COLORIT); 2020 May 8 [cited 2020 August 26].

Available from:


ColchiVID



double-blind,

placebo-

controlled

(174, anticipated)

> 70 years old, CrCL <

30 mL/min, liver

failure, CYP3A4

inhibitor use

Colchicine

1.5mg loading

dose, then

0.5mg BID for

10 days

1) Number of

patients with

improvement in

body

temperature,

myalgia,

arthralgia, total

lymphocyte

count, D-dimer,

fibrinogen, and

ferritin, 2)

Progression to

severe disease

None Ongoing d-dimer,

ferritin,

fibrinogen

ClinicalTrials.gov [Internet]. Mexico City, Mexico: National

Library of Medicine (US). 2020

April 29. Identifier NCT04367168. Colchicine Twice Daily During 10

Days as an Option for the Treatment

of Symptoms Induced by

Inflammation in Patients With Mild

and Severe Coronavirus Disease

(ColchiVID); 2020 May 27 [cited

2020 August 26]. Available from: https://clinicaltrials.gov/ct2/show/N

CT04367168.

COLCOVIDBD

(July 4, 2020 to present)

Early

Inpatient

Randomized,

double-blind,

placebo-

controlled

(300, anticipated)

Hepatic failure, eGFR

<30 mL/min,

decompensated heart

failure, QTc > 450 ms,

IBD, chemotherapy

use

Colchicine

1.2mg BID for

1 day, then

0.6mg daily for

13 days

Time to

deterioration by

2 points on 7-

grade clinical

status scale.

1) LOS, 2)

Supplemental oxygen,

3) Mechanical

ventilation, 4)

Mortality

Ongoing None ClinicalTrials.gov [Internet]. Dhaka,

Bangladesh: National Library of

Medicine (US). 2020 August 26. Identifier NCT04527562.

Colchicine in Moderate

Symptomatic COVID-19 Patients: Double Blind, Randomized, Placebo

Controlled Trial to Observe the

Efficacy (COLCOVIDBD); 2020

July 4 [cited 2020 August 26]. Available from:


CT04527562.



https://clinicaltrials.gov/ct2/show/NCT04355143

https://clinicaltrials.gov/ct2/show/NCT04355143

Page 5

Della-Torre et al.

(Published May 31, 2020)

Outpatient Non-randomized,

open label case

series

(9)

None Colchicine 1mg

BID for 1 day,

then 1mg daily

until afebrile

for 3 days

One patient

hospitalized for 4

days

2 patients with mild

diarrhea

None Della-Torre E, Della-Torre F,

Kusanovic M, et al. Treating

COVID-19 with colchicine in community healthcare setting. Clin

Immunol. 2020;217:108490.

COLCORONA

(March 23, 2020 to

present)

Early

Outpatient

Randomized,

double-blind,

placebo-

controlled

(6000,

anticipated)

40 years old, no

high-risk criteria,

unstable, IBD,

neuromuscular disease,

eGFR <30 mL/min,

cirrhosis, liver injury,

chemotherapy use

Colchicine

0.5mg BID for

3 days, then

0.5mg daily for

27 days

Composite:

Hospitalization

or Death

1) All-cause mortality,

2) Hospitalization, 3)

Ventilation

Ongoing None ClinicalTrials.gov [Internet].

Montreal, Canada (Global sites):

National Library of Medicine (US). 2020 March 26. Identifier

NCT04322682. Colchicine

Coronavirus SARS-CoV2 Trial

(COLCORONA) (COVID-19); 2020 March 23 [cited 2020 August

26]. Available from:


ACTCOVID19


Early

Outpatient

and Early

Inpatient

Randomized,

open-label

colchicine vs

IFN-beta vs ASA

vs rivaroxaban vs

usual care

(4000,

anticipated)

No high-risk criteria,

advanced kidney

disease, advanced liver

disease, CYP3A4

inhibitor use,

therapeutic

anticoagulation or

antiplatelets

Outpatient:

Colchicine

0.6mg BID for

3 days, then

0.6mg daily for

25 days.

Inpatient:

1.2mg loading

dose, then

0.6mg 2 hours

later, then

0.6mg BID for

28 days

Outpatient:

Composite

hospitalization or

death; Inpatient:

Composite:

mechanical

ventilation or

death

1) Clinical

deterioration by WHO,

2) Composite: MACE

Ongoing None ClinicalTrials.gov [Internet]. Ontario, Canada: National Library

of Medicine (US). 2020 March 27.

Identifier NCT04324463. Anti-Coronavirus Therapies to Prevent

Progression of Coronavirus Disease

2019 (COVID-19) Trial (ACTCOVID19); 2020 April 21


from:


COLCHI-COVID


Early

Outpatient

Randomized,

open-label vs

usual care

(1028,

anticipated)

70 years old, no

high-risk criteria,

severe gastrointestinal

disease, neuromuscular

disease, eGFR <30

mL/min, cirrhosis,

liver injury,

chemotherapy use,


Colchicine

0.5mg BID for

3 days, then

0.5mg daily for

18 days

1) Mortality, 2)

Hospitalization

None Ongoing None ClinicalTrials.gov [Internet].

Cantabria, Spain: National Library

of Medicine (US). 2020 June 4. Identifier NCT04416334.

PREEMPTIVE THERAPY WITH

COLCHICINE IN PATIENTS OLDER THAN 70 YEARS WITH

HIGH RISK OF SEVERE

PNEUMONIAE DUE TO

CORONAVIRUS (COLCHI-COVID); 2020 May 25 [cited 2020

August 26]. Available from:




Documents

Anti-inflammatory therapy for COVID-19 infection: the case